The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Jun Wang - One of the best experts on this subject based on the ideXlab platform.
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whole brain mapping of direct inputs to dopamine d1 and d2 receptor expressing medium spiny neurons in the posterior Dorsomedial Striatum
Eneuro, 2021Co-Authors: Yifeng Cheng, Britton Barbee, Xuehua Wang, Kayla Woodson, Emily Disney, Xueyi Xie, Jordan Bonifacio, Mariam Zaidi, Jun WangAbstract:The posterior Dorsomedial Striatum (pDMS) is mainly composed of medium spiny neurons (MSNs) expressing either dopamine D1 receptors (D1Rs) or D2Rs. Activation of these two MSN types produces opposing effects on addictive behaviors. However, it remains unclear whether pDMS D1-MSNs or D2-MSNs receive afferent inputs from different brain regions or whether the extrastriatal afferents express distinct dopamine receptors. To assess whether these afferents also contained D1Rs or D2Rs, we generated double transgenic mice, in which D1R-expressing and D2R-expressing neurons were fluorescently labeled. We used rabies virus-mediated retrograde tracing in these mice to perform whole-brain mapping of direct inputs to D1-MSNs or D2-MSNs in the pDMS. We found that D1-MSNs preferentially received inputs from the secondary motor, secondary visual, and cingulate cortices, whereas D2-MSNs received inputs from the primary motor and primary sensory cortices, and the thalamus. We also discovered that the bed nucleus of the stria terminalis (BNST) and the central nucleus of the amygdala (CeA) contained abundant D2R-expressing, but few D1R-expressing, neurons in a triple transgenic mouse model. Remarkably, although limited D1R or D2R expression was observed in extrastriatal neurons that projected to D1-MSNs or D2-MSNs, we found that cortical structures preferentially contained D1R-expressing neurons that projected to D1-MSNs or D2-MSNs, while the thalamus, substantia nigra pars compacta (SNc), and BNST had more D2R-expressing cells that projected to D2-MSNs. Taken together, these findings provide a foundation for future understanding of the pDMS circuit and its role in action selection and reward-based behaviors.
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alcohol intake enhances glutamatergic transmission from d2 receptor expressing afferents onto d1 receptor expressing medium spiny neurons in the Dorsomedial Striatum
Neuropsychopharmacology, 2019Co-Authors: Yifeng Cheng, Xuehua Wang, Kayla Woodson, Craig Kemper, Emily Disney, Jun WangAbstract:Dopaminergic modulation of corticostriatal transmission is critically involved in reward-driven behaviors. This modulation is mainly mediated by dopamine D1 receptors (D1Rs) and D2Rs, which are highly expressed in medium spiny neurons (MSNs) of the Dorsomedial Striatum (DMS), a brain region essential for goal-directed behaviors and addiction. D1Rs and D2Rs are also present at presynaptic cortical terminals within the DMS. However, it is not known how addictive substances alter the glutamatergic strength of striatal synapses expressing presynaptic dopamine receptors. Using cell type-specific Cre mice in combination with optogenetic techniques, we measured glutamatergic transmission at D1R- or D2R-expressing afferents to DMS MSNs. We found larger excitatory postsynaptic currents at the synapses between the extra-striatal D2R-expressing afferents and D1R-expressing MSNs (D2→D1), as compared with those observed at the other tested synapses (D1→D1, D1→D2, and D2→D2). Additionally, excessive alcohol consumption induced a long-lasting potentiation of glutamatergic transmission at the corticostriatal D2→D1 synapse. Furthermore, we demonstrated that activation of postsynaptic, but not presynaptic, D2Rs inhibited corticostriatal transmission in an endocannabinoid-dependent manner. Taken together, these data provide detailed information on the mechanisms underlying dopamine receptor-mediated modulation of brain reward circuitry.
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prenatal exposure to alcohol induces functional and structural plasticity in dopamine d1 receptor expressing neurons of the Dorsomedial Striatum
Alcoholism: Clinical and Experimental Research, 2018Co-Authors: Yifeng Cheng, Xuehua Wang, Xiaoyan Wei, Xueyi Xie, Sebastian Melo, Rajesh C Miranda, Jun WangAbstract:Background Prenatal alcohol exposure (PAE) is a leading cause of hyperactivity in children. Excitation of dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) of the Dorsomedial Striatum (DMS), a brain region that controls voluntary behavior, is known to induce hyperactivity in mice. We therefore hypothesized that PAE-linked hyperactivity was due to persistently altered glutamatergic activity in DMS D1-MSNs. Methods Female Ai14 tdTomato reporter mice were given access to alcohol in an intermittent access, 2-bottle choice paradigm before pregnancy, and following mating with male D1-Cre mice, through the pregnancy period, and until postnatal day (P) 10. Locomotor activity was tested in juvenile (P21) and adult (P133) offspring, and alcohol-conditioned place preference (CPP) was measured in adult offspring. Glutamatergic activity in DMS D1-MSNs of adult PAE and control mice was measured by slice electrophysiology, followed by measurements of dendritic morphology. Results Our voluntary maternal alcohol consumption model resulted in increased locomotor activity in juvenile PAE mice, and this hyperactivity was maintained into adulthood. Furthermore, PAE resulted in a higher alcohol-induced CPP in adult offspring. Glutamatergic activity onto DMS D1-MSNs was also enhanced by PAE. Finally, PAE increased dendritic complexity in DMS D1-MSNs in adult offspring. Conclusions Our model of PAE does result in persistent hyperactivity in offspring. In adult PAE offspring, hyperactivity is accompanied by potentiated glutamatergic strength and afferent connectivity in DMS D1-MSNs, an outcome that is also consistent with the observed increase in alcohol preference in PAE offspring. Consequently, a PAE-sensitive circuit, centered within the D1-MSN, may be linked to behavioral outcomes of PAE.
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alcohol induces input specific aberrant synaptic plasticity in the rat Dorsomedial Striatum
Neuropharmacology, 2017Co-Authors: Britton Barbee, Xuehua Wang, Jun WangAbstract:Accumulated evidence suggests that the Dorsomedial Striatum (DMS) of the basal ganglia plays an essential role in pathological excessive alcohol consumption. The DMS receives multiple glutamatergic inputs. However, whether and how alcohol consumption distinctly affects these excitatory afferents to the DMS remains unknown. Here, we used optogenetics to selectively activate the rat medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) inputs in DMS slices, and measured the effects of alcohol consumption on glutamatergic transmission in these corticostriatal and amygdalostriatal circuits. We found that excessive alcohol consumption increased AMPA receptor- and NMDA receptor (NMDAR)-mediated neurotransmission, as well as the GluN2B/NMDAR ratio, at the corticostriatal input to the DMS. The probability of glutamate release was increased selectively at the amygdalostriatal input. Interestingly, we discovered that paired activation of the mPFC and BLA inputs using dual-channel optogenetics induced robust long-term potentiation (LTP) of the corticostriatal input to the DMS. Taken together, these results indicate that excessive alcohol consumption potentiates glutamatergic transmission via a postsynaptic mechanism for the corticostriatal input and via a presynaptic mechanism for the amygdalostriatal input. These changes may in turn contribute to pathological alcohol consumption.
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alcohol elicits functional and structural plasticity selectively in dopamine d1 receptor expressing neurons of the Dorsomedial Striatum
The Journal of Neuroscience, 2015Co-Authors: Xuehua Wang, Jun Wang, Sami Ben Hamida, Yifeng Cheng, Emily Roltsch Hellard, Hannah Gil, Dorit RonAbstract:Addiction is thought to be a maladaptive form of learning and memory caused by drug-evoked aberrant synaptic plasticity. We previously showed that alcohol facilitates synaptic plasticity in the Dorsomedial Striatum (DMS), a brain region that drives goal-directed behaviors. The majority of DMS cells are medium spiny neurons (MSNs) that express dopamine D1 receptors (D1Rs) or D2 receptors (D2Rs), which drive “Go” or “No-Go” behaviors, respectively. Here, we report that alcohol induces cell type-specific synaptic and structural plasticity in the DMS. Using mice that express a fluorescence marker to visualize D1R or D2R MSNs, we show that repeated cycles of systemic administration of alcohol or alcohol consumption induces a long-lasting increase in AMPAR activity specifically in DMS D1R but not in D2R MSNs. Importantly, we report that alcohol consumption increases the complexity of dendritic branching and the density of mature mushroom-shaped spines selectively in DMS D1R MSNs. Finally, we found that blockade of D1R but not D2R activity in the DMS attenuates alcohol consumption. Together, these data suggest that alcohol intake produces profound functional and structural plasticity events in a subpopulation of neurons in the DMS that control reinforcement-related learning. SIGNIFICANCE STATEMENT Alcohol addiction is considered maladaptive learning and memory processes. Here we unraveled a long-lasting cellular mechanism that may contribute to the memory of alcohol-seeking behaviors. Specifically, we found that alcohol consumption produces a long-lasting enhancement of channel activity and persistent alterations of neuronal morphology in a part of the brain (DMS) that controls alcohol-drinking behaviors. Furthermore, we show that these alterations occur only in a subpopulation of neurons that positively control reward and reinforcement of drugs of abuse. Finally, we report that blocking the activity of this neuronal population reduces alcohol intake. As such synaptic and structural changes are the cellular hallmarks of learning and memory, and these neuroadaptations may drive the development of pathological heavy alcohol consumption.
Michael E Ragozzino - One of the best experts on this subject based on the ideXlab platform.
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cognitive flexibility deficits following 6 ohda lesions of the rat Dorsomedial Striatum
Neuroscience, 2018Co-Authors: Gena M Grospe, Phillip M Baker, Michael E RagozzinoAbstract:Parkinson's disease (PD) is a neurodegenerative disorder marked by severe motor deficits and reduced striatal dopamine levels. PD patients also commonly exhibit cognitive flexibility impairments, e.g., probabilistic reversal learning deficits that limit daily living. However, less is known about how decreased striatal dopamine signaling affects cognitive flexibility. Past studies indicate that the rat Dorsomedial Striatum is a striatal subregion that supports cognitive flexibility. Because PD patients exhibit probabilistic reversal learning deficits, the present experiment investigated whether the neurotoxin 6-hydroxydopamine (6-OHDA) injected into the Dorsomedial Striatum of male Long-Evans rats affects the acquisition and/or reversal learning of a spatial discrimination using a probabilistic learning procedure (80/20). Behavioral testing was conducted in a cross maze that occurred across two consecutive days. Rats with 6-OHDA lesions were not impaired on acquisition, but were impaired in reversal learning compared to that of sham controls. In reversal learning, Dorsomedial striatal dopamine depletion led to initial perseveration of the previously correct choice pattern, as well as an impairment in maintaining the new choice pattern after initially selected (regressive errors). A 6-OHDA lesion in the Dorsomedial Striatum also significantly increased 'lose-shift' probabilities in reversal learning suggesting that reduced dopamine signaling in this striatal area increased sensitivity to negative feedback ultimately impairing the maintenance of a new response pattern. Overall, the findings suggest that dopamine reduction in this striatal subregion can serve as a useful model to test novel treatments for ameliorating cognitive flexibility deficits in PD.
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5ht2a receptor blockade in Dorsomedial Striatum reduces repetitive behaviors in btbr mice
Genes Brain and Behavior, 2017Co-Authors: Dionisio A Amodeo, Elaine Rivera, Edwin H Cook, John A Sweeney, Michael E RagozzinoAbstract:Restricted and repetitive behaviors are a defining feature of autism, which can be expressed as a cognitive flexibility deficit or stereotyped, motor behaviors. There is limited knowledge about the underlying neuropathophysiology contributing to these behaviors. Previous findings suggest that central 5HT2A receptor activity is altered in autism, while recent work indicates that systemic 5HT2A receptor antagonist treatment reduces repetitive behaviors in an idiopathic model of autism. 5HT2A receptors are expressed in the orbitofrontal cortex and Striatum. These two regions have been shown to be altered in autism. The present study investigated whether 5HT2A receptor blockade in the Dorsomedial Striatum or orbitofrontal cortex in the BTBR mouse strain, an idiopathic model of autism, affects the phenotype related to restricted and repetitive behaviors. Microinfusion of the 5HT2A receptor antagonist, M100907 into the Dorsomedial Striatum alleviated a reversal learning impairment and attenuated grooming behavior. M100907 infusion into the orbitofrontal cortex increased perseveration during reversal learning and potentiated grooming. These findings suggest that increased 5HT2A receptor activity in the Dorsomedial Striatum may contribute to behavioral inflexibility and stereotyped behaviors in the BTBR mouse. 5HT2A receptor signaling in the orbitofrontal cortex may be critical for inhibiting a previously learned response during reversal learning and expression of stereotyped behavior. The present results suggest which brain areas exhibit abnormalities underlying repetitive behaviors in an idiopathic mouse model of autism, as well as which brain areas systemic treatment with M100907 may principally act on in BTBR mice to attenuate repetitive behaviors.
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contralateral disconnection of the rat prelimbic cortex and Dorsomedial Striatum impairs cue guided behavioral switching
Learning & Memory, 2014Co-Authors: Phillip M Baker, Michael E RagozzinoAbstract:Switches in reward outcomes or reward-predictive cues are two fundamental ways in which information is used to flexibly shift response patterns. The rat prelimbic cortex and Dorsomedial Striatum support behavioral flexibility based on a change in outcomes. The present experiments investigated whether these two brain regions are necessary for conditional discrimination performance in which a switch in reward-predictive cues occurs every three to six trials. The GABA agonists baclofen and muscimol infused into the prelimbic cortex significantly impaired performance leading rats to adopt an inappropriate turn strategy. The NMDA receptor antagonist D-AP5 infused into the Dorsomedial Striatum or prelimbic cortex and Dorsomedial Striatum contralateral disconnection impaired performance due to a rat failing to switch a response choice for an entire trial block in about two out of 13 test blocks. In an additional study, contralateral disconnection did not affect nonswitch discrimination performance. The results suggest that the prelimbic cortex and Dorsomedial Striatum are necessary to support cue-guided behavioral switching. The prelimbic cortex may be critical for generating alternative response patterns while the Dorsomedial Striatum supports the selection of an appropriate response when cue information must be used to flexibly switch response patterns.
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acetylcholine activity in selective striatal regions supports behavioral flexibility
Neurobiology of Learning and Memory, 2009Co-Authors: Michael E Ragozzino, Eric G Mohler, Margaret Prior, Carlos A Palencia, Suzanne RozmanAbstract:Daily living often requires individuals to flexibly respond to new circumstances. There is considerable evidence that the Striatum is part of a larger neural network that supports flexible adaptations. Cholinergic interneurons are situated to strongly influence striatal output patterns which may enable flexible adaptations. The present experiments investigated whether acetylcholine actions in different striatal regions support behavioral flexibility by measuring acetylcholine efflux during place reversal learning. Acetylcholine efflux selectively increased in the Dorsomedial Striatum, but not dorsolateral or ventromedial Striatum during place reversal learning. In order to modulate the M2-class of autoreceptors, administration of oxotremorine sesquifumurate (100 nM) into the Dorsomedial Striatum, concomitantly impaired reversal learning and an increase in acetylcholine output. These effects were reversed by the m2 muscarinic receptor antagonist, AF-DX-116 (20 nM). The effects of oxotremorine sesquifumurate and AF-DX-116 on acetylcholine efflux were selective to behaviorally-induced changes as neither treatment affected acetylcholine output in a resting condition. In contrast to reversal learning, acetylcholine efflux in the Dorsomedial Striatum did not change during place acquisition. The results reveal an essential role for cholinergic activity and define its locus of control to the Dorsomedial Striatum in cognitive flexibility.
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differential involvement of m1 type and m4 type muscarinic cholinergic receptors in the Dorsomedial Striatum in task switching
Neurobiology of Learning and Memory, 2008Co-Authors: Martha F Mccool, Sima Patel, Ravi Talati, Michael E RagozzinoAbstract:Previous experiments have demonstrated that the rat Dorsomedial Striatum is one brain area that plays a crucial role in learning when conditions require a shift in strategies. Further evidence indicates that muscarinic cholinergic receptors in this brain area support adaptations in behavioral responses. Unknown is whether specific muscarinic receptor subtypes in the Dorsomedial Striatum contribute to a flexible shift in response patterns. The present experiments investigated whether blockade of M1-type and/or M4-type cholinergic receptors in the Dorsomedial Striatum underlie place reversal learning. Experiment 1 investigated the effects of the M1-type muscarinic cholinergic antagonist, muscarinic-toxin 7 (MT-7) infused into the Dorsomedial Striatum in place acquisition and reversal learning. Experiment 2 investigated the effects of the M4-type muscarinic cholinergic antagonist, muscarinic-toxin 3 (MT-3) injected into the Dorsomedial Striatum in place acquisition and reversal learning. All testing occurred in a modified cross-maze across two consecutive sessions. Bilateral injections of MT-7 into the Dorsomedial Striatum at 1 or 2 μg, but not 0.05 μg impaired place reversal learning. Analysis of the errors revealed that MT-7 at 1 and 2 μg significantly increased regressive errors, but not perseverative errors. An injection of MT-7 2 μg into the Dorsomedial Striatum prior to place acquisition did not affect learning. Experiment 2 revealed that Dorsomedial striatal injections of MT-3 (0.05, 1 or 2 μg) did not affect place acquisition or reversal learning. The findings suggest that activation of M1-type muscarinic cholinergic receptors in the Dorsomedial Striatum, but not M4-type muscarinic cholinergic receptors facilitate the flexible shifting of response patterns by maintaining or learning a new choice pattern once selected.
Dorit Ron - One of the best experts on this subject based on the ideXlab platform.
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camp fyn signaling in the Dorsomedial Striatum direct pathway drives excessive alcohol use
Neuropsychopharmacology, 2021Co-Authors: Yann Ehinger, Nadege Morisot, Khanhky Phamluong, Samuel A Sakhai, Drishti Soneja, Martin F Adrover, Veronica A Alvarez, Dorit RonAbstract:Fyn kinase in the Dorsomedial Striatum (DMS) of rodents plays a central role in mechanisms underlying excessive alcohol intake. The DMS is comprised of medium spiny neurons (MSNs) that project directly (dMSNs) or indirectly (iMSNs) to the substantia nigra. Here, we examined the cell-type specificity of Fyn's actions in alcohol use. First, we knocked down Fyn selectively in DMS dMSNs or iMSNs of mice and measured the level of alcohol consumption. We found that downregulation of Fyn in dMSNs, but not in iMSNs, reduces excessive alcohol but not saccharin intake. D1Rs are coupled to Gαs/olf, which activate cAMP signaling. To examine whether Fyn's actions are mediated through cAMP signaling, DMS dMSNs were infected with GαsDREADD, and the activation of Fyn signaling was measured following CNO treatment. We found that remote stimulation of cAMP signaling in DMS dMSNs activates Fyn and promotes the phosphorylation of the Fyn substrate, GluN2B. In contract, remote activation of GαsDREADD in DLS dMSNs did not alter Fyn signaling. We then tested whether activation of GαsDREADD in DMS dMSNs or iMSNs alters alcohol intake and observed that CNO-dependent activation of GαsDREADD in DMS dMSNs but not iMSNs increases alcohol but not saccharin intake. Finally, we examined the contribution of Fyn to GαsDREADD-dependent increase in alcohol intake, and found that systemic administration of the Fyn inhibitor, AZD0503 blocks GαsDREADD-dependent increase in alcohol consumption. Our results suggest that the cAMP-Fyn axis in the DMS dMSNs is a molecular transducer of mechanisms underlying the development of excessive alcohol consumption.
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camp fyn signaling in the Dorsomedial Striatum direct pathway drives excessive alcohol use
bioRxiv, 2020Co-Authors: Yann Ehinger, Nadege Morisot, Khanhky Phamluong, Samuel A Sakhai, Martin F Adrover, Veronica A Alvarez, Dorit RonAbstract:Fyn kinase in the Dorsomedial Striatum (DMS) of rodents plays a central role in mechanisms underlying excessive alcohol intake. The DMS is comprised mostly of medium spiny neurons (MSNs) that are divided into dopamine D1 receptor expressing neurons (dMSNs), and dopamine D2 receptor expressing neurons (iMSNs). Here, we examined the cell-type specificity of Fyn9s actions on the development of alcohol use. First, we knocked down Fyn selectively in DMS dMSNs or iMSNs of mice and measured the level of alcohol consumption. We found that downregulation of Fyn in dMSNs, but not in iMSNs, reduces excessive alcohol but not saccharin intake and preference. D1Rs are coupled to Gs/olf, which activate cAMP signaling. To examine whether Fyn9s actions are mediated through cAMP signaling, DMS dMSNs were infected with GsDREADD, and the activation of Fyn signaling was measured following CNO treatment. We found that remote stimulation of cAMP signaling in DMS dMSNs activates Fyn and promotes the phosphorylation of the Fyn substrate, GluN2B. Next, we tested whether remote activation of GsDREADD in DMS dMSNs or iMSNs alters alcohol intake, and observed that CNO-dependent activation of GsDREADD in DMS dMSNs but not iMSNs increases alcohol but not saccharin intake and preference. Finally, we examined the contribution of Fyn to GsDREADD-dependent increase in alcohol intake, and found that systemic administration of the Fyn inhibitor, AZD0503 blocks GsDREADD-dependent increase in alcohol consumption. Our results suggest that the cAMP-Fyn axis in the DMS dMSNs is a molecular transducer of mechanisms underlying the development of excessive alcohol consumption.
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mtorc2 in the Dorsomedial Striatum of mice contributes to alcohol dependent f actin polymerization structural modifications and consumption
Neuropsychopharmacology, 2018Co-Authors: Sophie Laguesse, Nadege Morisot, Khanhky Phamluong, Samuel A Sakhai, Dorit RonAbstract:Actin is highly enriched at dendritic spines, and actin remodeling plays an essential role in structural plasticity. The mammalian target of rapamycin complex 2 (mTORC2) is a regulator of actin polymerization. Here, we report that alcohol consumption increases F-actin content in the Dorsomedial Striatum (DMS) of mice, thereby altering dendritic spine morphology in a mechanism that requires mTORC2. Specifically, we found that excessive alcohol consumption increases mTORC2 activity in the DMS, and that knockdown of Rictor, an essential component of mTORC2 signaling, reduces actin polymerization, and attenuates the alcohol-dependent alterations in spine head size and the number of mushroom spines. Finally, we show that knockdown of Rictor in the DMS reduces alcohol consumption, whereas intra-DMS infusion of the mTORC2 activator, A-443654, increases alcohol intake. Together, these results suggest that mTORC2 in the DMS facilitates the formation of F-actin, which in turn induces changes in spine structure to promote and/or maintain excessive alcohol intake.
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alcohol elicits functional and structural plasticity selectively in dopamine d1 receptor expressing neurons of the Dorsomedial Striatum
The Journal of Neuroscience, 2015Co-Authors: Xuehua Wang, Jun Wang, Sami Ben Hamida, Yifeng Cheng, Emily Roltsch Hellard, Hannah Gil, Dorit RonAbstract:Addiction is thought to be a maladaptive form of learning and memory caused by drug-evoked aberrant synaptic plasticity. We previously showed that alcohol facilitates synaptic plasticity in the Dorsomedial Striatum (DMS), a brain region that drives goal-directed behaviors. The majority of DMS cells are medium spiny neurons (MSNs) that express dopamine D1 receptors (D1Rs) or D2 receptors (D2Rs), which drive “Go” or “No-Go” behaviors, respectively. Here, we report that alcohol induces cell type-specific synaptic and structural plasticity in the DMS. Using mice that express a fluorescence marker to visualize D1R or D2R MSNs, we show that repeated cycles of systemic administration of alcohol or alcohol consumption induces a long-lasting increase in AMPAR activity specifically in DMS D1R but not in D2R MSNs. Importantly, we report that alcohol consumption increases the complexity of dendritic branching and the density of mature mushroom-shaped spines selectively in DMS D1R MSNs. Finally, we found that blockade of D1R but not D2R activity in the DMS attenuates alcohol consumption. Together, these data suggest that alcohol intake produces profound functional and structural plasticity events in a subpopulation of neurons in the DMS that control reinforcement-related learning. SIGNIFICANCE STATEMENT Alcohol addiction is considered maladaptive learning and memory processes. Here we unraveled a long-lasting cellular mechanism that may contribute to the memory of alcohol-seeking behaviors. Specifically, we found that alcohol consumption produces a long-lasting enhancement of channel activity and persistent alterations of neuronal morphology in a part of the brain (DMS) that controls alcohol-drinking behaviors. Furthermore, we show that these alterations occur only in a subpopulation of neurons that positively control reward and reinforcement of drugs of abuse. Finally, we report that blocking the activity of this neuronal population reduces alcohol intake. As such synaptic and structural changes are the cellular hallmarks of learning and memory, and these neuroadaptations may drive the development of pathological heavy alcohol consumption.
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inhibition of striatal enriched tyrosine phosphatase 61 in the Dorsomedial Striatum is sufficient to increased ethanol consumption
Journal of Neurochemistry, 2014Co-Authors: Emmanuel Darcq, Sami Ben Hamida, Viktor Kharazia, Khanky Phamluong, Paul Lombroso, Dorit RonAbstract:The STriatal-Enriched protein tyrosine Phosphatase 61 (STEP61) inhibits the activity of the tyrosine kinase Fyn and dephosphorylates the GluN2B subunit of the NMDA receptor, whereas the protein kinase A phosphorylation of STEP61 inhibits the activity of the phosphatase (Pharmacol. Rev., 64, 2012, p. 65). Previously, we found that ethanol activates Fyn in the Dorsomedial Striatum (DMS) leading to GluN2B phosphorylation, which, in turn, underlies the development of ethanol intake (J. Neurosci., 30, 2010, p. 10187). Here, we tested the hypothesis that inhibition of STEP61 by ethanol is upstream of Fyn/GluN2B. We show that exposure of mice to ethanol increased STEP61 phosphorylation in the DMS, which was maintained after withdrawal and was not observed in other striatal regions. Specific knockdown of STEP61 in the DMS of mice enhanced ethanol-mediated Fyn activation and GluN2B phosphorylation, and increased ethanol intake without altering the level of water, saccharine, quinine consumption or spontaneous locomotor activity. Together, our data suggest that blockade of STEP61 activity in response to ethanol is sufficient for the activation of the Fyn/GluN2B pathway in the DMS. Being upstream of Fyn and GluN2B, inactive STEP61 in the DMS primes the induction of ethanol intake. We show that ethanol-mediated inhibition of STEP61 in the DMS leads to Fyn activation and GluN2B phosphorylation. (a) Under basal conditions, active STEP61 inhibits Fyn activity and dephosphorylates GluN2B. (b) Ethanol leads to the phosphorylation of STEP61 on a specific inhibitory site. The inhibition of STEP61 activity contributes to the activation of Fyn in response to ethanol, which, in turn, phosphorylates GluN2B. These molecular adaptations in the DMS promote ethanol drinking.
Yifeng Cheng - One of the best experts on this subject based on the ideXlab platform.
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optogenetic induction of orbitostriatal long term potentiation in the Dorsomedial Striatum elicits a persistent reduction of alcohol seeking behavior in rats
Neuropharmacology, 2021Co-Authors: Yifeng Cheng, Xuehua Wang, Kayla Woodson, Xueyi Xie, Sebastian Melo, Himanshu Gangal, Wei Wang, Jared Jerger, Eric Garr, Yufei HuangAbstract:Abstract Uncontrolled drug-seeking and -taking behaviors are generally driven by maladaptive corticostriatal synaptic plasticity. The orbital frontal cortex (OFC) and its projections to the Dorsomedial Striatum (DMS) have been extensively implicated in drug-seeking and relapse behaviors. The influence of the synaptic plasticity of OFC projections to the DMS (OFC→DMS) on drug-seeking and -taking behaviors has not been fully characterized. To investigate this, we trained rats to self-administer 20% alcohol and then delivered an in vivo optogenetic protocol designed to induce long-term potentiation (LTP) selectively at OFC→DMS synapses. We selected LTP induction because we found that voluntary alcohol self-administration suppressed OFC→DMS transmission and LTP may normalize this transmission, consequently reducing alcohol-seeking behavior. Importantly, ex vivo slice electrophysiology studies confirmed that this in vivo optical stimulation protocol resulted in a significant increase in excitatory OFC→DMS transmission strength on day two after stimulation, suggesting that LTP was induced in vivo. Rat alcohol-seeking and -taking behaviors were significantly reduced on days 1–3, but not on days 7–11, after LTP induction. Striatal synaptic plasticity is modulated by several critical neurotransmitter receptors, including dopamine D1 receptors (D1Rs) and adenosine A2A receptors (A2ARs). We found that delivery of in vivo optical stimulation in the presence of a D1R antagonist abolished the LTP-associated decrease in alcohol-seeking behavior, whereas delivery in the presence of an A2AR antagonist may facilitate this LTP-induced behavioral change. These results demonstrate that alcohol-seeking behavior was negatively regulated by the potentiation of excitatory OFC→DMS neurotransmission. Our findings provide direct evidence that the OFC exerts “top-down” control of alcohol-seeking behavior via the DMS.
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whole brain mapping of direct inputs to dopamine d1 and d2 receptor expressing medium spiny neurons in the posterior Dorsomedial Striatum
Eneuro, 2021Co-Authors: Yifeng Cheng, Britton Barbee, Xuehua Wang, Kayla Woodson, Emily Disney, Xueyi Xie, Jordan Bonifacio, Mariam Zaidi, Jun WangAbstract:The posterior Dorsomedial Striatum (pDMS) is mainly composed of medium spiny neurons (MSNs) expressing either dopamine D1 receptors (D1Rs) or D2Rs. Activation of these two MSN types produces opposing effects on addictive behaviors. However, it remains unclear whether pDMS D1-MSNs or D2-MSNs receive afferent inputs from different brain regions or whether the extrastriatal afferents express distinct dopamine receptors. To assess whether these afferents also contained D1Rs or D2Rs, we generated double transgenic mice, in which D1R-expressing and D2R-expressing neurons were fluorescently labeled. We used rabies virus-mediated retrograde tracing in these mice to perform whole-brain mapping of direct inputs to D1-MSNs or D2-MSNs in the pDMS. We found that D1-MSNs preferentially received inputs from the secondary motor, secondary visual, and cingulate cortices, whereas D2-MSNs received inputs from the primary motor and primary sensory cortices, and the thalamus. We also discovered that the bed nucleus of the stria terminalis (BNST) and the central nucleus of the amygdala (CeA) contained abundant D2R-expressing, but few D1R-expressing, neurons in a triple transgenic mouse model. Remarkably, although limited D1R or D2R expression was observed in extrastriatal neurons that projected to D1-MSNs or D2-MSNs, we found that cortical structures preferentially contained D1R-expressing neurons that projected to D1-MSNs or D2-MSNs, while the thalamus, substantia nigra pars compacta (SNc), and BNST had more D2R-expressing cells that projected to D2-MSNs. Taken together, these findings provide a foundation for future understanding of the pDMS circuit and its role in action selection and reward-based behaviors.
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alcohol intake enhances glutamatergic transmission from d2 receptor expressing afferents onto d1 receptor expressing medium spiny neurons in the Dorsomedial Striatum
Neuropsychopharmacology, 2019Co-Authors: Yifeng Cheng, Xuehua Wang, Kayla Woodson, Craig Kemper, Emily Disney, Jun WangAbstract:Dopaminergic modulation of corticostriatal transmission is critically involved in reward-driven behaviors. This modulation is mainly mediated by dopamine D1 receptors (D1Rs) and D2Rs, which are highly expressed in medium spiny neurons (MSNs) of the Dorsomedial Striatum (DMS), a brain region essential for goal-directed behaviors and addiction. D1Rs and D2Rs are also present at presynaptic cortical terminals within the DMS. However, it is not known how addictive substances alter the glutamatergic strength of striatal synapses expressing presynaptic dopamine receptors. Using cell type-specific Cre mice in combination with optogenetic techniques, we measured glutamatergic transmission at D1R- or D2R-expressing afferents to DMS MSNs. We found larger excitatory postsynaptic currents at the synapses between the extra-striatal D2R-expressing afferents and D1R-expressing MSNs (D2→D1), as compared with those observed at the other tested synapses (D1→D1, D1→D2, and D2→D2). Additionally, excessive alcohol consumption induced a long-lasting potentiation of glutamatergic transmission at the corticostriatal D2→D1 synapse. Furthermore, we demonstrated that activation of postsynaptic, but not presynaptic, D2Rs inhibited corticostriatal transmission in an endocannabinoid-dependent manner. Taken together, these data provide detailed information on the mechanisms underlying dopamine receptor-mediated modulation of brain reward circuitry.
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prenatal exposure to alcohol induces functional and structural plasticity in dopamine d1 receptor expressing neurons of the Dorsomedial Striatum
Alcoholism: Clinical and Experimental Research, 2018Co-Authors: Yifeng Cheng, Xuehua Wang, Xiaoyan Wei, Xueyi Xie, Sebastian Melo, Rajesh C Miranda, Jun WangAbstract:Background Prenatal alcohol exposure (PAE) is a leading cause of hyperactivity in children. Excitation of dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) of the Dorsomedial Striatum (DMS), a brain region that controls voluntary behavior, is known to induce hyperactivity in mice. We therefore hypothesized that PAE-linked hyperactivity was due to persistently altered glutamatergic activity in DMS D1-MSNs. Methods Female Ai14 tdTomato reporter mice were given access to alcohol in an intermittent access, 2-bottle choice paradigm before pregnancy, and following mating with male D1-Cre mice, through the pregnancy period, and until postnatal day (P) 10. Locomotor activity was tested in juvenile (P21) and adult (P133) offspring, and alcohol-conditioned place preference (CPP) was measured in adult offspring. Glutamatergic activity in DMS D1-MSNs of adult PAE and control mice was measured by slice electrophysiology, followed by measurements of dendritic morphology. Results Our voluntary maternal alcohol consumption model resulted in increased locomotor activity in juvenile PAE mice, and this hyperactivity was maintained into adulthood. Furthermore, PAE resulted in a higher alcohol-induced CPP in adult offspring. Glutamatergic activity onto DMS D1-MSNs was also enhanced by PAE. Finally, PAE increased dendritic complexity in DMS D1-MSNs in adult offspring. Conclusions Our model of PAE does result in persistent hyperactivity in offspring. In adult PAE offspring, hyperactivity is accompanied by potentiated glutamatergic strength and afferent connectivity in DMS D1-MSNs, an outcome that is also consistent with the observed increase in alcohol preference in PAE offspring. Consequently, a PAE-sensitive circuit, centered within the D1-MSN, may be linked to behavioral outcomes of PAE.
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alcohol elicits functional and structural plasticity selectively in dopamine d1 receptor expressing neurons of the Dorsomedial Striatum
The Journal of Neuroscience, 2015Co-Authors: Xuehua Wang, Jun Wang, Sami Ben Hamida, Yifeng Cheng, Emily Roltsch Hellard, Hannah Gil, Dorit RonAbstract:Addiction is thought to be a maladaptive form of learning and memory caused by drug-evoked aberrant synaptic plasticity. We previously showed that alcohol facilitates synaptic plasticity in the Dorsomedial Striatum (DMS), a brain region that drives goal-directed behaviors. The majority of DMS cells are medium spiny neurons (MSNs) that express dopamine D1 receptors (D1Rs) or D2 receptors (D2Rs), which drive “Go” or “No-Go” behaviors, respectively. Here, we report that alcohol induces cell type-specific synaptic and structural plasticity in the DMS. Using mice that express a fluorescence marker to visualize D1R or D2R MSNs, we show that repeated cycles of systemic administration of alcohol or alcohol consumption induces a long-lasting increase in AMPAR activity specifically in DMS D1R but not in D2R MSNs. Importantly, we report that alcohol consumption increases the complexity of dendritic branching and the density of mature mushroom-shaped spines selectively in DMS D1R MSNs. Finally, we found that blockade of D1R but not D2R activity in the DMS attenuates alcohol consumption. Together, these data suggest that alcohol intake produces profound functional and structural plasticity events in a subpopulation of neurons in the DMS that control reinforcement-related learning. SIGNIFICANCE STATEMENT Alcohol addiction is considered maladaptive learning and memory processes. Here we unraveled a long-lasting cellular mechanism that may contribute to the memory of alcohol-seeking behaviors. Specifically, we found that alcohol consumption produces a long-lasting enhancement of channel activity and persistent alterations of neuronal morphology in a part of the brain (DMS) that controls alcohol-drinking behaviors. Furthermore, we show that these alterations occur only in a subpopulation of neurons that positively control reward and reinforcement of drugs of abuse. Finally, we report that blocking the activity of this neuronal population reduces alcohol intake. As such synaptic and structural changes are the cellular hallmarks of learning and memory, and these neuroadaptations may drive the development of pathological heavy alcohol consumption.
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neurotoxic damage to the Dorsomedial Striatum exaggerates the behavioral influence of a context specific inhibitory association mediated by the ventral hippocampus
Behavioral Neuroscience, 2008Co-Authors: Robert J Mcdonald, Amy L King, Nancy S HongAbstract:This study investigated the role of the Dorsomedial Striatum (DMS) on the acquisition of a context-specific inhibitory association acquired during training on a simple visual discrimination task. The authors have previously shown that this inhibitory association depends on the circuitry of the ventral hippocampus. The authors were interested in the anatomical and functional relationship between the hippocampus and DMS and the potential contribution the DMS makes to this inhibitory behavior. Rats with neurotoxic lesions of the DMS, or shams, were assessed on the acquisition of a visual discrimination task. Following asymptotic performance, they were given reversal training in the same or different context from the original training. The results indicated that the rats with DMS damage showed an exaggerated context-specific inhibition effect. The rats with DMS damage were also impaired on a simultaneously trained tactile/spatial discrimination, a functional effect linked to a neural circuit that includes the dorsal hippocampus. A discussion of potential pathways and mechanisms for these different effects is presented.
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lesions of the dorsolateral or Dorsomedial Striatum impair performance of a previously acquired simple discrimination task
Neurobiology of Learning and Memory, 2005Co-Authors: Robert E Featherstone, Robert J McdonaldAbstract:Previous evidence has suggested a specific role for the dorsal Striatum, especially the dorsolateral region of the dorsal Striatum, in stimulus-response learning. In a previous study, we found an impairment in animals with dorsolateral striatal lesions on a simple discrimination task (CS+/CS-), thought to require the involvement of both stimulus-reward and stimulus-response learning. It is possible that the generally poor performance of dorsolateral lesioned animals on this experiment precluded adequate exposure to stimulus-reward pairings necessary for solving this task, and, thus, had little to do with stimulus-response learning. To test this hypothesis, the performance of animals with dorsolateral and Dorsomedial striatal lesions was assessed on a previously acquired simple discrimination task. To independently assess the effects of each lesion on the performance of stimulus-reward learning, dorsolateral and Dorsomedial lesioned animals were assessed on a previously acquired conditioned place preference task (CPP). In agreement with our earlier experiment, and the stimulus-response interpretation of dorsolateral striatal function, animals with dorsolateral striatal lesions were found to be impaired during post-lesion performance of the simple discrimination task, but not CPP learning. Additionally, Dorsomedial lesioned animals were found to be impaired in performance of the simple discrimination task, but not on the CPP task. Possible explanations for the differences between the role of the Dorsomedial Striatum in acquisition and expression of the simple discrimination task are proposed.
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Dorsal Striatum and stimulus-response learning: lesions of the dorsolateral, but not Dorsomedial, Striatum impair acquisition of a simple discrimination task.
Behavioural brain research, 2004Co-Authors: Robert E Featherstone, Robert J McdonaldAbstract:In the present experiment, the effects of neurotoxic lesions (quinolinic acid) of the dorsolateral or Dorsomedial Striatum were investigated on a simple instrumental discrimination task (CS+/CS-). Rats with lesions of the dorsolateral Striatum were found to be impaired in the acquisition of this task, as compared to rats with either Dorsomedial striatal or sham lesions. Furthermore, dorsolateral striatal lesioned animals had significantly lower levels of responding across the course of discrimination training, as assessed both by overall rate of response during CS+ presentations and number of CS+ trials without a response, despite having shown levels of responding during variable interval training that did not differ from that of sham lesioned animals. In contrast, animals with lesions of the Dorsomedial Striatum did not show an impairment in acquisition of the present task, but had slightly higher rates of responding during CS- presentations. It is argued that the poor acquisition and low response rates observed in animals with dorsolateral striatal lesions reflect a failure in stimulus-response learning, while the performance of animals with Dorsomedial striatal lesions may have been the result of an increase in overall activity rate.
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dorsal Striatum and stimulus response learning lesions of the dorsolateral but not Dorsomedial Striatum impair acquisition of a stimulus response based instrumental discrimination task while sparing conditioned place preference learning
Neuroscience, 2004Co-Authors: Robert E Featherstone, Robert J McdonaldAbstract:While some evidence suggests that the dorsal Striatum is important for stimulus-response learning, disagreement exists about the relative contribution of the dorsolateral and Dorsomedial Striatum to this form of learning. In the present experiment, the effects of lesions of the dorsolateral and Dorsomedial Striatum were investigated on two tasks that differentially require the development of stimulus-response learning. The first task utilized an operant conditional discrimination task, which is likely to rely heavily upon stimulus-response learning. The second task looked conditioned place preference learning, a task that is unlikely to require the development of stimulus-response associations. Animals with lesions of the dorsolateral Striatum were impaired on the operant conditional discrimination task, but retained the ability to learn the conditioned place preference task. In contrast, animals with lesions of the Dorsomedial Striatum were not found to be impaired on either task used in the present experiment. These results suggest that the dorsolateral Striatum is necessary for the successful acquisition of tasks that place a demand upon stimulus-response learning, while the Dorsomedial Striatum is not involved in this type of learning.