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D2R striatopallidal neurons inhibit both locomotor and drug reward processes

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Pierre F Durieux
Pierre F Durieux
Pierre F Durieux
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Bertrand Bearzatto at Université Catholique de Louvain - UCLouvain
Bertrand Bearzatto
Stefania Guiducci at Università degli Studi di Modena e Reggio Emilia
Stefania Guiducci
Thorsten Buch at University of Zurich
Thorsten Buch
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The specific functions of dopamine D(2) receptor-positive (D(2)R) striatopallidal neurons remain poorly understood. Using a genetic mouse model, we found that ablation of D(2)R neurons in the entire striatum induced hyperlocomotion, whereas ablation in the ventral striatum increased amphetamine conditioned place preference. Thus D(2)R striatopallidal neurons limit both locomotion and, unexpectedly, drug reinforcement.
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D2R striatopallidal neurons
inhibit both locomotor and
drug reward processes
Pierre F Durieux1, Bertrand Bearzatto1, Stefania Guiducci2,
Thorsten Buch3, Ari Waisman4, Michele Zoli2,
Serge N Schiffmann1,5 & Alban de Kerchove d’Exaerde1,5
The specific functions of dopamine D2receptor–positive (D2R)
striatopallidal neurons remain poorly understood. Using a
genetic mouse model, we found that ablation of D2R neurons in
the entire striatum induced hyperlocomotion, whereas ablation
in the ventral striatum increased amphetamine conditioned
place preference. Thus D2R striatopallidal neurons limit both
locomotion and, unexpectedly, drug reinforcement.
The striatum is critically involved in motor and motivational func-
tions1,2. The dorsal striatum, caudate-putamen, isprimarily implicated
in motor control and the learning of habits and skills, whereas
the ventral striatum, the nucleus accumbens (NAc), is essential for
motivation and drug reinforcement1,3. Striatal dysfunction has been
demonstrated in movement disorders, including Parkinson’s and
Huntington’s disease, and in psychiatric disorders, such as schizophre-
nia and drug addiction4.
The GABA medium-sized spiny neurons (MSNs, about 95% of
striatal neurons), which are targets of the cerebral cortex and the
midbrain dopaminergic neurons, form two pathways5.Thedopamine
D1receptor–positive (D1R) striatonigral MSNs project to the medial
globus pallidus and substantia nigra pars reticulata (direct pathway)
and coexpress dopamine D1receptors and substance P, whereas D2R
striatopallidal MSNs project to the lateral globus pallidus (indirect
pathway) and coexpress dopamine D2receptor, adenosine A2A receptor
(A2AR) and enkephalin (Enk). The specific role of the two efferent
pathways in motor and motivational control remains poorly under-
stood. D1R striatonigral and D2R striatopallidal neurons, which are
intermingled and morphologically indistinguishable, cannot be func-
tionally dissociated with techniques such as chemical lesions or surgery
and the currently available tools for selective targeting of these
populations are unsatisfactory. The Drd1a-andDrd2-egfp transgenic
mice obtained by BAC transgenesis6have recently shed some light on
the role of MSN subpopulations or genes in striatal pathophysio-
logy7–10. In regards to their role in motivation and drug addiction,
current studies are focused mostly on the D1R striatonigral neurons2.
To assess the role of D2R striatopallidal neurons, we selectively
ablated these cells in adult mice by Cre-mediated expression of a
diphtheria toxin receptor (DTR) and diphtheria toxin injection11
(Supplementary Methods online). All animal procedures were
approved by the Universite
´Libre de Bruxelles School of Medicine
Ethical Committee. We generated mice expressing Cre recombinase
under the control of the Adora2a (A2AR) promoter (Adora2a-cre mice,
Supplementary Fig. 1 online) by BAC transgenesis. A2AR was chosen
because it is expressed more in D2R neurons than in any other brain
area12 and, in contrast to D2R, A2AR is supposed to not be expressed in
striatal cholinergic interneurons and mesostriatal dopaminergic cells.
In Adora2a-cre mice mated with a Rosa26-LacZ reporter strain,
b-galactosidase staining was only found in striatal Enk-positive cells
(Supplementary Fig. 1), indicating that Cre was selectively expressed
in D2R striatopallidal neurons.
Adora2a-cre mice were crossed with mice in which the expression of
a simian DTR (Hbegf ) gene from a ubiquitously active promoter is
prevented by a loxP-flanked stop cassette (inducible DTR mice,
iDTR)11, leading to double transgenic Adora2a-cre/+; iDTR/+ mice
(DTR-positive mice) that selectively expressed DTR in D2Rstriatopal-
lidal neurons (Supplementar y Fig. 2 online). Toxin was stereotaxically
injected into the striatum to produce unilateral or bilateral ablation of
D2R neurons in the entire striatum (full ablation) or in the NAc (NAc
ablation). We analyzed the kinetics of D2R striatopallidal ablation in
DTR-positive mice with unilateral striatum diphtheria toxin injections
by quantifying A2AR binding sites from 3–28 d after diphtheria toxin
injections (Fig. 1a–c). The injected side showed a 65% and 45%
reduction in A2AR binding in the dorsal and ventral striatum, respec-
tively, at 7 d after injections, and an almost complete loss of striatal
A2AR binding (97% in dorsal and 87% in ventral striatum) from 14 d
after diphtheria toxin injections, with no reduction in striatonigral
neuron–specific D1Rbinding(Fig. 1a–c). We found no changes in
binding sites in diphtheria toxin–injected control littermates lacking
DTR expression (Adora2a-cre–/–;iDTR/+; DTR negative mice) or in
saline-injected DTR-positive mice. The disappearance of D2Rstriato-
pallidal neuron mRNAs (D2R, A2AR and Enk) and the preservation of
D1R striatonigral neuron mRNAs (D1R and substance P) on the
injected side at 14 d after injections (Fig. 1d,e) confirmed the specificity
of the lesion. The same pattern of ablation was detected from
the anterior to the posterior striatum (Supplementar y Fig. 3 online).
The four subpopulations of striatal interneurons remained intact
(Supplementary Fig. 4 online).
In light of the connections between midbrain dopamine and striatal
neurons, we investigated the consequences of D2R striatopallidal
neuron loss on the mesostriatal dopamine system. Bilateral full ablation
of D2R striatopallidal neurons did not modify cell body or terminal
dopaminergic markers (Supplementary Fig. 5 online). To assess
dopaminergic function in vivo, we carried out intrastriatal micro-
dialysis in bilateral diphtheria toxin–injected DTR-positive and
Received 19 December 2008; accepted 28 January 2009; published online 8 March 2009; doi:10.1038/nn.2286
1Laboratory of Neurophysiology, Universite
´Libre de Bruxelles, Brussels, Belgium. 2Department of Biomedical Sciences, Section of Physiology, University of Modena and
Reggio Emilia, Modena, Italy. 3Department of Pathology, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. 4First Medical Department,
Johannes Gutenberg University of Mainz, Mainz, Germany. 5These authors contributed equally to this work. Correspondence should be addressed to A.d.K.d.E.
(adekerch@ulb.ac.be).
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DTR-negative mice. No difference in basal dopamine extracellular
concentration or in amphetamine (AMPH)-induced dopamine over-
flow was found between the two genotypes (Supplementary
Fig. 5). These results indicate that D2R striatopallidal neuron ablation
does not induce major modifications in striatal dopaminergic function.
As D2R neurons send GABAergic projections to GABA neurons of
the globus pallidus, we assessed the effect of bilateral D2Rneuronloss
on glutamic acid decarboxylase isoform 67 mRNA levels in the globus
pallidus as an indirect index of GABA neuron activity13 (Supplemen-
tary Fig. 6 online). We found an increase in glutamic acid decarbox-
ylase isoform 67 mRNA in the globus pallidus of DTR-positive mice as
compared with DTR-negative mice, confirming that the D2R striato-
pallidal neurons exert inhibitory control on globus pallidus GABA
neuron activity.
Locomotor activity in open fieldboxes was recorded daily for 30 min
(Fig. 2) in mice that underwent bilateral full striatum diphtheria toxin
injections. Starting at 6 d after diphtheria toxin injections, DTR-
positive mice became threefold to fourfold more active than controls
(Supplementary Video 1 online). This hyperactivity was stable
through day 16 (Fig. 2c) and DTR-positive mice were still hyperactive
(207 ± 19% of control level) 33 d after diphtheria toxin injection (data
not shown). These results demonstrate the inhibitory function of the
D2R striatopallidal neurons on locomotor activity.
As the ventral striatum is the key neuronal substrate for drug
reinforcement3,wecarriedoutaNAcD
2R striatopallidal neuron
ablation in DTR-positive mice (Fig. 2d,e). Enk mRNA levels in the
ventral striatum of diphtheria toxin–injected DTR-positive mice
decreased by 80% compared with control diphtheria toxin–injected
DTR-negative mice. We found a 30% reduction in Enk mRNA in the
dorsal striatum, selectively in its rostral part. Because dorsal striatum
shows progressive rostro-caudal enlargement, this limited rostral loss
modestly influenced the overall number of D2R striatopallidal neurons
in the dorsal striatum. NAc ablation did not show spontaneous
hyperlocomotion (Supplementary Fig. 7 online), demonstrating that
the NAc ablation of D2R striatopallidal neurons is functionally different
from the full ablation. NAc DTR-positive mice were examined in an
AMPH (1, 3 or 5 mg per kg) conditioned place preference (CPP)
procedure followed by an examination of CPP extinction over 1 week
(Fig. 2f). The DTR-positive mice showed a higher preference for the
AMPH-paired compartment as compared with controls on the first test
day (2 d after the last AMPH injection) and maintained greater CPP on
the following test days (4 and 9 d after last AMPH injection) (see
Supplementary Methods for statistical analyses). Note that there was a
loss of CPP for DTR-negative mice on day 9 (AMPH 1 and 3 mg per
kg), whereas DTR-positive mice still showed a preference for the
AMPH-paired compartment.
In summary, our results provide direct experimental evidence that
D2R striatopallidal neurons are critical for both the control of motor
behavior and drug reinforcement. The Adora2a-cre/+;iDTR/+ mouse,
allowing specific D2R striatopallidal neuron ablation, confirmed that
D1R–substance P–expressing and D2R-A2AR-Enk–expressing neurons
in the striatum are largely segregated. This model shows the advantage
of A2AR- over D2R-targeted transgenic mice for targeting D2Rstriato-
pallidal neurons, as A2AR does not target striatal cholinergic interneur-
ons and dopaminergic afferents14, thus avoiding cholinergic alterations
and distinguishing between post- and presynaptic dopaminergic
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DTR+ saline D1R
Figure 1 Characterization of D2R striatopallidal neuron ablation after full striatum unilateral diphtheria toxin injections in DTR-positive mice (coronal sections,
level +1.2 mm relative to bregma). (a) Autoradiograms of A2ARs and D1Rs, markers of D2R striatopallidal and D1R striatonigral neurons, respectively, from
3–28 d after unilateral full striatum diphtheria toxin injections in DTR-positive (DTR+) mice, showing kinetics and specificity of the D2R striatopallidal neuron
ablation. (b,c)A
2ARandD
1R binding levels in the dorsal (b) and ventral (c) striatum of diphtheria toxin (DT)-injected DTR-positive mice and controls
(diphtheria toxin–injected DTR-negative (DTR–) or saline-injected DTR-positive mice) (n¼39 in each group). (d)In situ hybridization autoradiograms of
D2R striatopallidal (A2AR, D2R and Enk) and D1R striatonigral (D1R and substance P) neuron mRNAs at 14 d after unilateral full striatum diphtheria toxin
injections. (e) Striatopallidal (A2AR, D2R and Enk) and striatonigral (D1R and substance P) neuron mRNA levels at 14 d after diphtheria toxin injections (n¼7
in each group). Data are expressed as optical density values of the injected side in percent of the uninjected side. Arrows indicate the injected side. Scale bars
represent 1 mm. Data are reported as mean ± s.e.m. *** Po0.001 (as compared with diphtheria toxin–injected DTR-injected mice); ** P o0.001 (as
compared with saline-injected DTR-positive mice).
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mechanisms. The complete bilateral ablation of these neurons induces
persistent spontaneous hyperlocomotion, demonstrating a functional
effect of D2R striatopallidal neuron loss and validating the hypothesis
that A2AR-D2R–expressing neurons normally inhibit motor activity1.
The increase in AMPH CPP following ablation of D2R striatopallidal
neurons mainly in the NAc was unanticipated and is, to the best of our
knowledge, the first experimental demonstration that the pathway in
which these neurons take part normally inhibits drug reinforcement.
These data suggest that, similar to what has been observed for motor
control, reciprocal antagonism between D2R striatopallidal and
D1R striatonigral neurons is crucial for motivational processes and
reinforcement. The involvement of D2Rs in drug reward processes is
still puzzling15,asD
2Rs are expressed at many sites in the striatal
network. Our results suggest that the activation of postsynaptic D2Rs
on D2R striatopallidal neurons in the NAc facilitates drug reinforce-
ment by inhibiting these neurons4,15.
Together, these data show that Adora2a-cre/+;iDTR/+ mice are a
useful movement disorder model and underscore the need for char-
acterization of the specific cellular and molecular modifications that are
induced in D2R striatopallidal neurons by drugs of abuse.
Note: Supplementary information is available on the Nature Neuroscience website.
ACKNOWLEDGMENTS
We thank M. Picciotto for helpful and critical comments on the manuscript and
D. Houtteman, S. Laghmiri and L. Cuvelier for expert technical assistance. P.F.D.
is Research Fellow of the Fonds de la Recherche Scientifique (bourse de doctorat
Fonds de la Recherche Scientifique) and A.d.K.d.E. is a Research Associate of the
DTR–DTR+
DTR–DTR+
Enk
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caudal striatum
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***
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Dorsal Ventral
Figure 2 Behavioral consequences of D2R striatopallidal neuron removal and quantification of the D2R striatopallidal neuron ablation. (a)In situ hybridization
autoradiograms of Enk mRNA in rostral (level +1.2 mm relative to bregma) and caudal (level 0.1 mm relative to bregma) coronal brain sections of full striatum
diphtheria toxin–injected DTR-positive and DTR-negative mice. (b) Quantification of Enk mRNA levels in rostral and caudal striatum. Data are expressed as
optical density values of the injected striatum in DTR-positive in percent of DTR-negative mice (n¼611 per group). (c) Locomotor activity of DTR-positive
and control mice 3 d before to 16 d after full striatum bilateral diphtheria toxin injections (n¼17 in diphtheria toxin–injected DTR-positive group and n¼6
per group in control DTR-negative diphtheria toxin–injected and saline–injected DTR-positive groups). (d,e)In situ hybridization autoradiogr ams (d)ofEnk
mRNA in rostral (level +1.2 mm relative to bregma) and caudal (level 0.1 mm relative to bregma) coronal brain sections of NAc diphtheria toxin–injected DTR-
positive and DTR-negative mice and quantification of Enk mRNA levels (e). Data are expressed as optical density values of the injected striatum as a percentage
of DTR-negative mice (n¼34–39 per group). (f) CPP for AMPH of diphtheria toxin–injected DTR-positive and DTR-negative mice. Preference score was
measured at days 2, 4 and 9 after the last AMPH injection (n¼8–14 in each group). Arrows indicate the injected side. Scale bars represent 1 mm. Data are
reported as mean ± s.e.m. Statistical comparisons were made between diphtheria toxin–injected DTR-positive mice and respective control mice. * Po0.05,
*** Po0.001 (as compared with diphtheria toxin–injected DTR-positive mice); ** P o0.001 (as compared with saline-injected DTR-positive mice).
Fonds de la Recherche Scientifique (Belgium). This study was supported
by Fondation Me
´dicale Reine Elisabeth (Belgium), Fonds de la Recherche
Scientifique (Belgium), Fonds d’Encouragement a
`la Recherche from the
Universite
´Libre de Bruxelles, Action de Recherche Concerte
´e from the
Communaute
´Franc¸ aise Wallonie Bruxelles and Ministero Italiano dell’Universita
`
e della Ricerca (grant number PRIN20072BTSR2) to M.Z.
AUTHOR CONTRIBUTIONS
P.F.D., S.N.S. and A.d.K.d.E. conceived and designed the experiments. P.F.D.,
A.d.K.d.E., B.B. and S.G. carried out the experiments. T.B. and A.W. contributed
materials. P.F.D., M.Z., S.N.S. and A.d.K.d.E. analyzed the data and wrote the paper.
Published online at http://www.nature.com/natureneuroscience/
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... In the striatum, two distinct neuronal circuits, the direct and indirect pathways, play a critical role in locomotion. The direct pathway is responsible for the initiation of actions and requires the activity of dopamine 1 receptor expressing spiny projection neurons (D1-SPNs), whereas the inhibitory indirect pathway recruits striatal dopamine 2 receptor expressing (D2-) SPNs [33][34][35][36][37][38]. Previous studies have suggested an imbalance between the direct and the indirect pathway in NDDs [39][40][41][42]; however, a comprehensive understanding of the role of these pathways in mediating sex-specific effects on behavior is lacking. ...
... del/+ males. The traditional rate model of movement control suggests that the two major neuronal circuits in the striatum antagonize each other: the direct pathway (D1-SPNs) initiates movement, while the indirect pathway (D2-SPNs) suppresses it [35,36,77,78]. ...
... del/+ in D2-SPNs, we utilized A2a-cre mice instead of D2-cre mouse. It is because cre recombinase is expressed in striatal cholinergic interneurons as well as D2-SPNs [107], unlike A2a-cre mice, which directs D2-SPNs but not cholinergic interneurons [36]. Experimental data was collected from littermate animals during the same time period. ...
A chromosome region linked to neurodevelopmental disorders acts in distinct neuronal circuits in males and females to control locomotor behavior
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Biological sex shapes the manifestation and progression of neurodevelopmental disorders (NDDs). These disorders often demonstrate male-specific vulnerabilities; however, the identification of underlying mechanisms remains a significant challenge in the field. Hemideletion of the 16p11.2 region (16p11.2 del/+) is associated with NDDs, and mice modeling 16p11.2 del/+ exhibit sex-specific striatum-related phenotypes relevant to NDDs. Striatal circuits, crucial for locomotor control, consist of two distinct pathways: the direct and indirect pathways originating from D1 dopamine receptor (D1R) and D2 dopamine receptor (D2R) expressing spiny projection neurons (SPNs), respectively. In this study, we define the impact of 16p11.2 del/+ on striatal circuits in male and female mice. Using snRNA-seq, we identify sex- and cell type-specific transcriptomic changes in the D1- and D2-SPNs of 16p11.2 del/+ mice, indicating distinct transcriptomic signatures in D1-SPNs and D2-SPNs in males and females, with a ∼5-fold greater impact in males. Further pathway analysis reveals differential gene expression changes in 16p11.2 del/+ male mice linked to synaptic plasticity in D1- and D2-SPNs and GABA signaling pathway changes in D1-SPNs. Consistent with our snRNA-seq study revealing changes in GABA signaling pathways, we observe distinct changes in miniature inhibitory postsynaptic currents (mIPSCs) in D1- and D2-SPNs from 16p11.2 del/+ male mice. Behaviorally, we utilize conditional genetic approaches to introduce the hemideletion selectively in either D1- or D2-SPNs and find that conditional hemideletion of genes in the 16p11.2 region in D2-SPNs causes hyperactivity in male mice, but hemideletion in D1-SPNs does not. Within the striatum, hemideletion of genes in D2-SPNs in the dorsal lateral striatum leads to hyperactivity in males, demonstrating the importance of this striatal region. Interestingly, conditional 16p11.2 del/+ within the cortex drives hyperactivity in both sexes. Our work reveals that a locus linked to NDDs acts in different striatal circuits, selectively impacting behavior in a sex- and cell type-specific manner, providing new insight into male vulnerability for NDDs. Highlights - 16p11.2 hemideletion (16p11.2 del/+) induces sex- and cell type-specific transcriptomic signatures in spiny projection neurons (SPNs). - Transcriptomic changes in GABA signaling in D1-SPNs align with changes in inhibitory synapse function. - 16p11.2 del/+ in D2-SPNs causes hyperactivity in males but not females. - 16p11.2 del/+ in D2-SPNs in the dorsal lateral striatum drives hyperactivity in males. - 16p11.2 del/+ in cortex drives hyperactivity in both sexes. Graphic abstract
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... Moreover, we recapitulated most of the embryonic phenotypes and successfully rescued them with postnatal interventions using Cre virus restricted to the striatum. The Adora2a-Cre mouse line could serve as an alternate mouse model to avoid these possible confounds (89). ...
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... The reduction and refinement of the animal experiments was achieved by an ad hoc power calculation (N) and designing paired experiments if possible. Mouse strains used in the study are: C57Bl/6JRccHsd (B6, Envigo), Tg(Drd1-cre)EY262Gsat (Drd1-Cre, Gensat), Tg(Adora2a-cre)2MDkde (Adora2A-Cre(Durieux et al., 2009)), Oprm1-2A-Cre (Oprm1-Cre(Märtin et al., 2019)), B6.Cg-Gt(ROSA)26Sor tm14(CAG-tdTomato)Hze /J (Ai14, the Jackson Laboratory), B6J.Cg-Gt(ROSA)26Sor tm95.1(CAG-GCaMP6f)Hze /MwarJ (Ai95D, the Jackson Laboratory). ...
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Full-text available
  • Jan 2024
Spontaneous activity of neurons during early ontogenesis is instrumental for stabilization and refinement of developing neuronal connections. The role of spontaneous activity in synaptic development has been described in detail for cortical-like structures. Yet, very little is known about activity-dependent development of long-range inhibitory projections, such as projections from striatum. Here, we show that striatal projection neurons (SPNs) in dorsal striatum are spontaneously active in P4-P14 mice. Spontaneous activity was detected in both direct-pathway SPNs (dSPNs) and indirect-pathway SPNs (iSPNs). Most of the spontaneously active cells were in striosomes – a chemical compartment in striatum defined by expression of µ-opioid receptor. Higher excitability of both striosomal dSPNs and iSPNs was related to their intrinsic excitability properties (higher action potential half-width and IV slope). Tonic activation of muscarinic M1 receptor maintains the spontaneous activity of striosomal SPNs, the effect being stronger in iSPNs and weaker in dSPNs. To investigate if the neonatal spontaneous activity is needed for the stabilization of SPN long-range projections, we chemogenetically inhibited striosomal SPNs in neonatal animals and studied the efficiency of striatonigral projections in adult animals. Inhibition of striosomal SPNs by chronic CNO administration to P6-14 pups caused a reduction in the functional GABAergic innervation and in the density of gephyrin puncta in dopaminergic neurons of substantia nigra pars compacta of the adult (P52-79) animals. Chronic administration of CNO later in development (P21-29), on the contrary, resulted in higher mIPSC frequency in dopaminergic cells of the adult animals. Thus, the activity-dependent stabilization of striosomal projections has different developmental phases, and the long-term outcome of perturbations in these processes depends on the developmental period when they occur. Taken together, our results demonstrate that spontaneous activity of SPNs is essential for the maturation and stabilization of striatal efferents.
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... GAD2 is expressed in both Drd1+ and Drd2+ medium spiny neurons in the rodent striatum (Ferhat et al., 2023). Activation of Drd1+ neurons is known to promote locomotion (Freeze et al., 2013;Kravitz et al., 2010), whereas Drd2+ neuron activation and DRD2 agonism can inhibit locomotion (Barrozo et al., 2015;Durieux et al., 2009;Ford, 2014). Disruption of either cilia (through Ift88 knockout), or ciliary trafficking of GPCRs (via Bbs1 knockout), specifically on Drd1+ neurons leads to reductions in general locomotion (Stubbs et al., 2022b). ...
Cilia loss on distinct neuron populations differentially alters cocaine-induced locomotion and reward
Article
  • Dec 2023
Background: Neuronal primary cilia are being recognized for their role in mediating signaling associated with a variety of neurobehaviors, including responses to drugs of abuse. They function as signaling hubs, enriched with a diverse array of G-protein coupled receptors (GPCRs), including several associated with motivation and drug-related behaviors. However, our understanding of how cilia regulate neuronal function and behavior is still limited. Aims: The objective of the current study was to investigate the contributions of primary cilia on specific neuronal populations to behavioral responses to cocaine. Methods: To test the consequences of cilia loss on cocaine-induced locomotion and reward-related behavior, we selectively ablated cilia from dopaminergic or GAD2-GABAergic neurons in mice. Results: Cilia ablation on either population of neurons failed to significantly alter acute locomotor responses to cocaine at a range of doses. With repeated administration, mice lacking cilia on GAD2-GABAergic neurons showed no difference in locomotor sensitization to cocaine compared to wild-type (WT) littermates, whereas mice lacking cilia on dopaminergic neurons exhibited reduced locomotor sensitization to cocaine at 10 and 30 mg/kg. Mice lacking cilia on GAD2-GABAergic neurons showed no difference in cocaine conditioned place preference (CPP), whereas mice lacking cilia on dopaminergic neurons exhibited reduced CPP compared to WT littermates. Conclusions: Combined with previous findings using amphetamine, our results show that behavioral effects of cilia ablation are cell- and drug type-specific, and that neuronal cilia contribute to modulation of both the locomotor-inducing and rewarding properties of cocaine.
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... In contrast, dopamine D2 receptor (DRD2)expressing SPNs project to the external segment of the globus pallidus. It has been assumed that this pathway negatively modifies circuits from the basal ganglia to the cortical regions, leading to the suppression of movements [17,18,20,22,23,[31][32][33]. Defective DA signaling onto D1-and D2-expressing SPNs can, therefore, lead to both a reduction in voluntary movements and an increase in involuntary movements. ...
Dopaminergic Input Regulates the Sensitivity of Indirect Pathway Striatal Spiny Neurons to Brain-Derived Neurotrophic Factor
Article
Full-text available
  • Oct 2023
Simple Summary Motor dysfunction is among the main symptoms of Parkinson’s disease (PD). This is closely linked to the loss of the neurotransmitter dopamine (DA) in the midbrain and in the striatum. Additionally, the ability of striatal neurons to undergo adaptive cellular alterations and synaptic plasticity is impaired. Dopamine receptor D1 (DRD1) stimulation is needed for the establishment of long-term potentiation (LTP) at synapses of striatal spiny projection neurons (SPNs), which leads to enhanced neurotransmission. In contrast, dopamine receptor D2 (DRD2) stimulation is needed for the formation of long-term depression (LTD) in SPNs, which leads to the opposite effect. The tropomyosin receptor kinase B (TrkB) and its ligand brain-derived neurotrophic factor (BDNF) are centrally involved in plasticity regulation at the corticostriatal neurons synapses. There are two populations of striatal SPNs, with different projection targets in the brain. DRD1 is expressed in direct pathway spiny projection neurons (dSPNs) and its activation enhances TrkB sensitivity for BDNF by increasing the levels of TrkB at the cell surface. In this study, we showed that the activation of DRD2 in cultured striatal indirect pathway spiny projection neurons (iSPNs) and cholinergic interneurons causes the retraction of TrkB from the plasma membrane. This provides an explanation for the opposing synaptic plasticity changes observed upon DRD1 or DRD2 stimulation. In addition, TrkB was found within intracellular structures in dSPNs and iSPNs in Pitx3−/− mice, a genetic model of PD with early onset dopaminergic depletion in the dorsolateral striatum (DLS). This dysregulated BDNF/TrkB signaling might contribute to the pathophysiology of direct and indirect pathway striatal projection neurons in PD. Abstract Motor dysfunction in Parkinson’s disease (PD) is closely linked to the dopaminergic depletion of striatal neurons and altered synaptic plasticity at corticostriatal synapses. Dopamine receptor D1 (DRD1) stimulation is a crucial step in the formation of long-term potentiation (LTP), whereas dopamine receptor D2 (DRD2) stimulation is needed for the formation of long-term depression (LTD) in striatal spiny projection neurons (SPNs). Tropomyosin receptor kinase B (TrkB) and its ligand brain-derived neurotrophic factor (BDNF) are centrally involved in plasticity regulation at the corticostriatal synapses. DRD1 activation enhances TrkB’s sensitivity for BDNF in direct pathway spiny projection neurons (dSPNs). In this study, we showed that the activation of DRD2 in cultured striatal indirect pathway spiny projection neurons (iSPNs) and cholinergic interneurons causes the retraction of TrkB from the plasma membrane. This provides an explanation for the opposing synaptic plasticity changes observed upon DRD1 or DRD2 stimulation. In addition, TrkB was found within intracellular structures in dSPNs and iSPNs from Pitx3−/− mice, a genetic model of PD with early onset dopaminergic depletion in the dorsolateral striatum (DLS). This dysregulated BDNF/TrkB signaling might contribute to the pathophysiology of direct and indirect pathway striatal projection neurons in PD.
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... In the present studies, C57Bl/6 J mice (Jackson Labs), Pvalb tm1(cre)Arbr (PV Cre+) (Jackson Labs) [26], B6.FVB(Cg)-Tg(Drd1-cre) EY266Gsat/Mmucd (D1-Cre+) (MMMRC Repository), and B6.FVB (Cg)-Tg(Adora2a-cre)KG139Gsat/Mmucd (A2a-Cre) [14] (MMMRC Repository) mice were used for experiments. Adult (>8 weeks) male and female mice were housed in groups of 2-4, with mouse chow (Labdiet 5015) and water ad libitum, and were kept on a 14 hr light/10 hr dark cycle. ...
Chronic alcohol exposure differentially alters calcium activity of striatal cell populations during actions
Article
Full-text available
  • Sep 2023
Alcohol Use Disorder (AUD) can induce long lasting alterations to executive function. This includes altered action control, which can manifest as dysfunctional goal-directed control. Cortical and striatal circuits mediate goal-directed control over behavior, and prior research has found chronic alcohol disrupts these circuits. In particular, prior in vivo and ex vivo work have identified alterations to function and activity of dorsal medial striatum (DMS), which is necessary for goal-directed control. However, unknown is whether these alterations manifest as altered activity of select DMS populations during behavior. Here we examine effects of prior chronic alcohol exposure on calcium activity modulation during action-related behaviors via fiber photometry of genetically-identified DMS populations including the direct and indirect output pathways, and fast-spiking interneurons. We find that prior chronic alcohol exposure leads to increased calcium modulation of the direct pathway during action related behavior. In contrast, prior chronic alcohol exposure led to decreased calcium activity modulation of the indirect pathway and the fast-spiking interneuron population around action-related events. Together, our findings suggest an imbalance in striatal activity during action control. This disruption may contribute to the altered goal-directed control previously reported.
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Single-nucleus RNA sequencing of striatal microglia reveals distinct transcriptomic signatures of acute stress and chronic exercise
Preprint
  • Jun 2024
Severe acute stress can produce long lasting decreases in voluntary physical activity that contribute to degraded mental and physical health. Stress also produces enduring molecular changes in the striatum, a brain region that regulates voluntary wheel-running and other motivated behaviors. Microglia, the primary immune cells of the central nervous system, have specialized functions in responding to stress, sensing changes in the striatum, and controlling neuronal activity. Thus, microglia are positioned at the interface between neural responses to stress and neural coordination of voluntary activity; however, the role of striatal microglia in stress-induced long-term suppression of voluntary activity remains unexplored. The present study employs single nucleus RNA-sequencing to investigate how stress and exercise impact the biology of microglia in the striatum. We find that stress-induced decreases in running behavior are associated with specific microglial activation profiles. Furthermore, we show that access to a running wheel is associated with an additional and distinct profile of microglia activation characterized by upregulation of complement components and phagocytosis pathways. Lastly, we find that distinct microglial gene sets are associated with general running (versus not running) and more subtle variation in genes with individual running levels. Taken together, our results contribute to a broader understanding of the diverse states that striatal microglia can assume in response to stress and exercise, and broadly suggest that microglia exhibit more nuanced functional responses to environmental perturbations than previously thought.
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Differential contribution of direct and indirect pathways from dorsolateral and dorsomedial striatum to motor symptoms in Huntington's disease mice
Preprint
Full-text available
  • Jun 2024
The alterations in the basal ganglia circuitry associated with motor symptoms in Huntington's Disease (HD) have been extensively investigated. Yet, the specific contribution of the direct and indirect striatal output pathways from the dorsolateral (DLS) and dorsomedial striatum (DMS) to the motor dysfunction is still not fully understood. Here, using the symptomatic R6/1 male mouse model of HD, strong functional connectivity alterations between DMS and DLS regions with the rest of brain were observed by fMRI, particularly pronounced in the DLS. Then, we systematically evaluated how the selective optogenetic stimulation of the direct and indirect pathways from DLS and DMS influences locomotion, exploratory behavior, and motor learning. In wild type (WT) mice, optogenetic stimulation of the direct pathway from DLS and the indirect pathway from DMS elicited subtle locomotor enhancements, while exploratory behavior remained unaltered. Additionally, stimulation of the indirect pathway from DLS improved the performance in the accelerated rotarod task. In contrast, in HD mice, optogenetic stimulation of the distinct striatal pathways did not modulate these behaviors. Overall, this study points to deficits in the integration of neuronal activity in HD mice, while it contributes to deeper understanding of the complexity of motor control by the diverse striatal subcircuits.
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Dopamine Receptor Type 2-Expressing Medium Spiny Neurons in the Ventral Lateral Striatum Have a Non-REM Sleep-Induce Function
Article
Full-text available
  • Sep 2023
Dopamine receptor type 2-expressing medium spiny neurons (D2-MSNs) in the medial part of the ventral striatum (VS) induce non-REM (NREM) sleep from the wake state in animals. However, it is unclear whether D2-MSNs in the lateral part of the VS (VLS), which is anatomically and functionally different from the medial part of the VS, contribute to sleep-wake regulation. This study aims to clarify whether and how D2-MSNs in the VLS are involved in sleep-wake regulation. Our study found that specifically removing D2-MSNs in the VLS led to an increase in wakefulness time in mice during the dark phase using a diphtheria toxin-mediated cell ablation/dysfunction technique. D2-MSN ablation throughout the VS further increased dark phase wakefulness time. These findings suggest that VLS D2-MSNs may induce sleep during the dark phase with the medial part of the VS. Next, our fiber photometric recordings revealed that the population intracellular calcium (Ca ²⁺ ) signal in the VLS D2-MSNs increased during the transition from wake to NREM sleep. The mean Ca ²⁺ signal level of VLS D2-MSNs was higher during NREM and REM sleep than during the wake state, supporting their sleep-inducing role. Finally, optogenetic activation of the VLS D2-MSNs during the wake state always induced NREM sleep, demonstrating the causality of VLS D2-MSNs activity with sleep induction. Additionally, activation of the VLS D1-MSNs, counterparts of D2-MSNs, always induced wake from NREM sleep, indicating a wake-promoting role. In conclusion, VLS D2-MSNs could have an NREM sleep-inducing function in coordination with those in the medial VS.
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Gerfen CR, Mahan LC, Susel Z, Chase TN, Monsma Jr FJ, Sibley DR. D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 250: 1429-1432
Article
Full-text available
  • Jan 1991
The striatum, which is the major component of the basal ganglia in the brain, is regulated in part by dopaminergic input from the substantia nigra. Severe movement disorders result from the loss of striatal dopamine in patients with Parkinson's disease. Rats with lesions of the nigrostriatal dopamine pathway caused by 6-hydroxydopamine (6-OHDA) serve as a model for Parkinson's disease and show alterations in gene expression in the two major output systems of the striatum to the globus pallidus and substantia nigra. Striatopallidal neurons show a 6-OHDA-induced elevation in their specific expression of messenger RNAs (mRNAs) encoding the D2 dopamine receptor and enkephalin, which is reversed by subsequent continuous treatment with the D2 agonist quinpirole. Conversely, striatonigral neurons show a 6-OHDA-induced reduction in their specific expression of mRNAs encoding the D1 dopamine receptor and substance P, which is reversed by subsequent daily injections of the D1 agonist SKF-38393. This treatment also increases dynorphin mRNA in striatonigral neurons. Thus, the differential effects of dopamine on striatonigral and striatopallidal neurons are mediated by their specific expression of D1 and D2 dopamine receptor subtypes, respectively.
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Adenosine A2 receptors regulate the gene expression of striatopallidal and striatonigral neurons
Article
Full-text available
  • Apr 1993
Adenosine acts as a neuromodulator through A1 and A2 receptors. The adenosine analogs have been recognized, among other effects, as strong depressors of the locomotor activity by acting on striatal A2 receptors. Moreover, the A2a receptor subtype is exclusively expressed in the striatum. To elucidate at the cellular level the roles of adenosine in the basal ganglia, the anatomical and functional relationships of the A2 receptors with the dopamine D1 and D2 receptors were studied in the rat striatum. In situ hybridization histochemistry was used either in combination with retrograde labeling of striatonigral neurons to determine the projection site of A2a receptor expressing neurons, or on consecutive thin sections to address the putative coexpression of the A2a receptor with the D1 or D2 receptors in individual neurons. The A2a receptor is mainly expressed by neurons projecting to the globus pallidus and expressing also the dopamine D2 receptor and enkephalin, but very sparsely by neurons projecting to the substantia nigra that express the dopamine D1 receptor and substance P. We have further examined the regulatory effect of the A2 receptors on striatal gene expression using in situ hybridization histochemistry and quantitative autoradiography. Rats unilaterally depleted in dopamine by an unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal pathway used as a model of Parkinson's disease subsequently received chronic injections of saline or the adenosine receptor antagonist caffeine. Intact rats were chronically treated with either saline, caffeine alone, caffeine with N-ethyl-carboxamidoadenosine (an equipotent A1 and A2 agonist), or caffeine with cyclohexyladenosine (a more selective A1 agonist).(ABSTRACT TRUNCATED AT 250 WORDS)
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Conditional Ablation of Striatal Neuronal Types Containing Dopamine D2 Receptor Disturbs Coordination of Basal Ganglia Function
Article
Full-text available
  • Nov 2003
  • J NEUROSCI
Dopamine (DA) exerts synaptic organization of basal ganglia circuitry through a variety of neuronal populations in the striatum. We performed conditional ablation of striatal neuronal types containing DA D2 receptor (D2R) by using immunotoxin-mediated cell targeting. Mutant mice were generated that express the human interleukin-2 receptor alpha-subunit under the control of the D2R gene. Intrastriatal immunotoxin treatment of the mutants eliminated the majority of the striatopallidal medium spiny neurons and cholinergic interneurons. The elimination of these neurons caused hyperactivity of spontaneous movement and reduced motor activation in response to DA stimulation. The elimination also induced upregulation of GAD gene expression in the globus pallidus (GP) and downregulation of cytochrome oxidase activity in the subthalamic nucleus (STN), whereas it attenuated DA-induced expression of the immediate-early genes (IEGs) in the striatonigral neurons. In addition, chemical lesion of cholinergic interneurons did not alter spontaneous movement but caused a moderate enhancement in DA-induced motor activation. This enhancement of the behavior was accompanied by an increase in the IEG expression in the striatonigral neurons. These data suggest that ablation of the striatopallidal neurons causes spontaneous hyperactivity through modulation of the GP and STN activity and that the ablation leads to the reduction in DA-induced behavior at least partly through attenuation of the striatonigral activity as opposed to the influence of cholinergic cell lesion. We propose a possible model in which the striatopallidal neurons dually regulate motor behavior dependent on the state of DA transmission through coordination of the basal ganglia circuitry.
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Gong S, Zheng C, Doughty ML, Losos K, Didkovsky N, Schambra UB, Nowak NJ, Joyner A, Leblanc G, Hatten ME, Heintz NA gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature 425:917-925
Article
Full-text available
  • Nov 2003
  • NATURE
The mammalian central nervous system (CNS) contains a remarkable array of neural cells, each with a complex pattern of connections that together generate perceptions and higher brain functions. Here we describe a large-scale screen to create an atlas of CNS gene expression at the cellular level, and to provide a library of verified bacterial artificial chromosome (BAC) vectors and transgenic mouse lines that offer experimental access to CNS regions, cell classes and pathways. We illustrate the use of this atlas to derive novel insights into gene function in neural cells, and into principal steps of CNS development. The atlas, library of BAC vectors and BAC transgenic mice generated in this screen provide a rich resource that allows a broad array of investigations not previously available to the neuroscience community.
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Regulation of drug-taking and -seeking behaviors by neuroadaptations in the mesolimbic dopamine system
Article
Full-text available
  • Feb 2004
  • NEUROPHARMACOLOGY
Previous studies have identified several neuroadaptations to chronic drug use, but relatively few have been functionally linked to addiction-related changes in drug-taking and -seeking behaviors. This article summarizes our past and present studies on the contribution of drug-induced neuroadaptations in the mesolimbic dopamine system to addiction-related changes in drug self-administration and the propensity for relapse in drug withdrawal. Our studies suggest that drug-induced up-regulation in cyclic AMP (cAMP)-protein kinase A (PKA) signaling in the nucleus accumbens (NAc) contributes to escalating drug intake and a propensity for relapse by differentially altering the sensitivity of D1 and D2 dopamine receptors that regulate drug-taking and -seeking behaviors. In addition, our studies suggest that drug-induced neuroplasticity at excitatory synapses in both the ventral tegmental area (VTA) and the NAc also facilitates drug-seeking behavior and the propensity for relapse. Finally, the role of both transient and enduring neuroadaptations in regulating drug-seeking behavior is discussed in view of different learning- and memory-based interactions.
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A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration
Article
Full-text available
  • Jul 2005
A new system for lineage ablation is based on transgenic expression of a diphtheria toxin receptor (DTR) in mouse cells and application of diphtheria toxin (DT). To streamline this approach, we generated Cre-inducible DTR transgenic mice (iDTR) in which Cre-mediated excision of a STOP cassette renders cells sensitive to DT. We tested the iDTR strain by crossing to the T cell- and B cell-specific CD4-Cre and CD19-Cre strains, respectively, and observed efficient ablation of T and B cells after exposure to DT. In MOGi-Cre/iDTR double transgenic mice expressing Cre recombinase in oligodendrocytes, we observed myelin loss after intraperitoneal DT injections. Thus, DT crosses the blood-brain barrier and promotes cell ablation in the central nervous system. Notably, we show that the developing DT-specific antibody response is weak and not neutralizing, and thus does not impede the efficacy of DT. Our results validate the use of iDTR mice as a tool for cell ablation in vivo.
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The Functional-Anatomy of Basal Ganglia Disorders
Article
  • Nov 1989
  • TRENDS NEUROSCI
Basal ganglia disorders are a heterogeneous group of clinical syndromes with a common anatomic locus within the basal ganglia. To account for the variety of clinical manifestations associated with insults to various parts of the basal ganglia we propose a model in which specific types of basal ganglia disorders are associated with changes in the function of subpopulations of striatal projection neurons. This model is based on a synthesis of experimental animal and post-mortem human anatomic and neurochemical data. Hyperkinetic disorders, which are characterized by an excess of abnormal movements, are postulated to result from the selective impairment of striatal neurons projecting to the lateral globus pallidus. Hypokinetic disorders, such as Parkinson's disease, are hypothesized to result from a complex series of changes in the activity of striatal projection neuron subpopulations resulting in an increase in basal ganglia output. This model suggests that the activity of subpopulations of striatal projection neurons is differentially regulated by striatal afferents and that different striatal projection neuron subpopulations may mediate different aspects of motor control.
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Chapter 9 Regulation of glutamic acid decarboxylase gene expression in efferent neurons of the basal ganglia
Article
  • Feb 1993
  • Progr Brain Res
The majority of efferent neurons of the striatum and of its main target areas, the pallidum and substantia nigra pars reticulata, are GABA-ergic. Therefore, GABA-ergic neurons constitute the backbone of the output system of the basal ganglia, and regulation of GABA synthesis is likely to play a critical role in the adaptation of basal ganglia neurons to physiological and pathological challenges. The limiting step in GABA synthesis is catalyzed by glutamic acid decarboxylase (GAD), an enzyme detected with immunohistochemical techniques in brain GABA-ergic neurons. In recent years, the changes in steady-state levels of GAD and its mRNA occurring in the basal ganglia have been examined in response to lesions of neuronal inputs and pharmacological treatments. The ultimate goal of this chapter is to provide new insights into the plasticity of GAD gene expression in the basal ganglia and its functional significance in neurodegenerative diseases and chronic drug therapy.
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The Basal ganglia
Article
  • Aug 2000
  • CURR BIOL
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