Selective filtering of excitatory inputs to nucleus accumbens by dopamine and serotonin

The detailed mechanisms by which dopamine (DA) and serotonin (5-HT) act in the nucleus accumbens (NAc) to influence motivated behaviors in distinct ways remain largely unknown. Here, we examined whether DA and 5-HT selectively modulate excitatory synaptic transmission in NAc medium spiny neurons in an input-specific manner. DA reduced excitatory postsynaptic currents (EPSCs) generated by paraventricular thalamus (PVT) inputs but not by ventral hippocampus (vHip), basolateral amygdala (BLA), or medial prefrontal cortex (mPFC) inputs. In contrast, 5-HT reduced EPSCs generated by inputs from all areas except the mPFC. Release of endogenous DA and 5-HT by methamphetamine (METH) and (±)3,4-methylenedioxymethamphetamine (MDMA), respectively, recapitulated these input-specific synaptic effects. Optogenetic inhibition of PVT inputs enhanced cocaine-conditioned place preference, whereas mPFC input inhibition reduced the enhancement of sociability elicited by MDMA. These findings suggest that the distinct, input-specific filtering of excitatory inputs in the NAc by DA and 5-HT contribute to their discrete behavioral effects.

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Cell-type and endocannabinoid specific synapse connectivity in the adult nucleus accumbens core

10.1101/613497 ◽

2019 ◽

Author(s):

Marion A. Deroche ◽

Olivier Lassalle ◽

Olivier J. Manzoni

Keyword(s):

Prefrontal Cortex ◽

Nucleus Accumbens ◽

Basolateral Amygdala ◽

Ventral Hippocampus ◽

Cb1 Receptors ◽

Medium Spiny Neurons ◽

Cell Type ◽

Spiny Neurons ◽

Trpv1 Receptors ◽

Specific Manner

ABSTRACTThe nucleus accumbens (NAc) is a mesocorticolimbic structure that integrates cognitive, emotional and motor functions. Although its role in psychiatric disorders is widely acknowledged, the understanding of its circuitry is not complete. Here we combined optogenetic and whole-cell recordings to draw a functional portrait of excitatory disambiguated synapses onto D1 and D2 medium spiny neurons (MSNs) in the adult mouse NAc core. Comparing synaptic properties of ventral hippocampus (vHipp), basolateral amygdala (BLA) and prefrontal cortex (PFC) inputs revealed a hierarchy of synaptic inputs and feedforward inhibition that depends on the identity of the postsynaptic target MSN. Thus, the BLA is the dominant excitatory pathway onto D1 MSNs (BLA > PFC = vHipp) while PFC inputs dominate D2 MSNs (PFC > vHipp > BLA). Feedforward inhibition of MSN firing too, was input and cell-type specific: while minimal at vHipp-D1 and vHipp-D2 inputs; it inhibited with similar efficacy BLA-D1 or BLA-D2 inputs, was minimal at PFC-D1 but maximal at PFC-D2 inputs. We also tested the hypothesis that endocannabinoids endow excitatory circuits with pathway- and cell-specific plasticity. Thus, while CB1 receptors (CB1R) uniformly depress excitatory pathways irrespective of MSNs identity, TRPV1 receptors (TRPV1R) bidirectionally control inputs onto the NAc core in a pathway-specific manner. Finally, we show how the interplay of TRPV1R/CB1R shapes plasticity at identified BLA-NAc synapses. Together these data shed new light on synapse and circuit specificity in the adult NAc core and illustrate how endocannabinoids contribute to pathway-specific synaptic plasticity.SIGNIFICANCE STATEMENTWe examined the impact of connections from the ventral hippocampus (vHipp,) basolateral amygdala (BLA) and prefrontal cortex (PFC) onto identified medium spiny neurons (MSN) in the adult accumbens core. We found BLA inputs were strongest at D1 MSNs while PFC inputs dominate D2 MSNs. We evaluated the role of the endocannabinoid system in pathway- and cell-specific plasticity and found that CB1 receptors (CB1R) and TRPV1 receptors (TRPV1R) bidirectionally control synaptic transmission and plasticity onto accumbens’ MSNs in a pathway- and cell-specific manner. Finally, we clarify how the interplay of TRPV1R/CB1R shapes plasticity at identified BLA-NAc synapses.

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Postnatal development of excitatory postsynaptic currents in nucleus accumbens medium spiny neurons

Neuroscience ◽

10.1016/j.neuroscience.2008.05.002 ◽

2008 ◽

Vol 154 (4) ◽

pp. 1440-1449 ◽

Cited By ~ 9

Author(s):

L. Zhang ◽

R.A. Warren

Keyword(s):

Nucleus Accumbens ◽

Postnatal Development ◽

Medium Spiny Neurons ◽

Excitatory Postsynaptic Currents ◽

Postsynaptic Currents ◽

Spiny Neurons

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Distinct role of nucleus accumbens D2-MSN projections to ventral pallidum in different phases of motivated behavior

10.1101/2020.11.27.401042 ◽

2020 ◽

Author(s):

Carina Soares-Cunha ◽

Raquel Correia ◽

Ana Verónica Domingues ◽

Bárbara Coimbra ◽

Nivaldo AP de Vasconcelos ◽

...

Keyword(s):

Nucleus Accumbens ◽

Behavioral Effect ◽

Ventral Pallidum ◽

Medium Spiny Neurons ◽

Motivated Behavior ◽

Spiny Neurons ◽

Reward Delivery ◽

Instrumental Task ◽

Motivated Behaviors

AbstractThe nucleus accumbens (NAc) is a key region in motivated behaviors. NAc medium spiny neurons (MSNs) are divided into those expressing dopamine receptor D1 or D2. Classically, D1- and D2-MSNs have been described as having opposing roles in reinforcement but recent evidence suggests a more complex role for D2-MSNs.Here we show that optogenetic modulation of D2-MSN to ventral pallidum (VP) projections during different stages of motivated behavior has contrasting effects in motivation. Activation of D2-MSN-VP projections during a reward-predicting cue results in increased motivational drive, whereas activation at reward delivery results in decreased motivation; optical inhibition has the opposite behavioral effect. In addition, in a free choice instrumental task, animals prefer the lever that originates one pellet in opposition to pellet plus D2-MSN-VP optogenetic activation, and vice versa for optogenetic inhibition.In summary, D2-MSN-VP projections play different (and even opposing) roles in distinct phases of motivated behavior.

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Nucleus accumbens medium spiny neurons subtypes signal both reward and aversion

Molecular Psychiatry ◽

10.1038/s41380-019-0484-3 ◽

2019 ◽

Vol 25 (12) ◽

pp. 3241-3255 ◽

Cited By ~ 8

Author(s):

Carina Soares-Cunha ◽

Nivaldo A. P. de Vasconcelos ◽

Bárbara Coimbra ◽

Ana Verónica Domingues ◽

Joana M. Silva ◽

...

Keyword(s):

Nucleus Accumbens ◽

Dopamine Receptor ◽

Opioid Receptors ◽

Positive Reinforcement ◽

Behavioral Effects ◽

Medium Spiny Neurons ◽

Prolonged Stimulation ◽

Spiny Neurons ◽

Dopaminergic Tone ◽

Neuronal Stimulation

AbstractDeficits in decoding rewarding (and aversive) signals are present in several neuropsychiatric conditions such as depression and addiction, emphasising the importance of studying the underlying neural circuits in detail. One of the key regions of the reward circuit is the nucleus accumbens (NAc). The classical view on the field postulates that NAc dopamine receptor D1-expressing medium spiny neurons (D1-MSNs) convey reward signals, while dopamine receptor D2-expressing MSNs (D2-MSNs) encode aversion. Here, we show that both MSN subpopulations can drive reward and aversion, depending on their neuronal stimulation pattern. Brief D1- or D2-MSN optogenetic stimulation elicited positive reinforcement and enhanced cocaine conditioning. Conversely, prolonged activation induced aversion, and in the case of D2-MSNs, decreased cocaine conditioning. Brief stimulation was associated with increased ventral tegmenta area (VTA) dopaminergic tone either directly (for D1-MSNs) or indirectly via ventral pallidum (VP) (for D1- and D2-MSNs). Importantly, prolonged stimulation of either MSN subpopulation induced remarkably distinct electrophysiological effects in these target regions. We further show that blocking κ-opioid receptors in the VTA (but not in VP) abolishes the behavioral effects induced by D1-MSN prolonged stimulation. In turn, blocking δ-opioid receptors in the VP (but not in VTA) blocks the behavioral effects elicited by D2-MSN prolonged stimulation. Our findings demonstrate that D1- and D2-MSNs can bidirectionally control reward and aversion, explaining the existence of controversial studies in the field, and highlights that the proposed striatal functional opposition needs to be reconsidered.

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The Sodium Channel β4 Auxiliary Subunit Selectively Controls Long-Term Depression in Core Nucleus Accumbens Medium Spiny Neurons

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2017.00017 ◽

2017 ◽

Vol 11 ◽

Cited By ~ 2

Author(s):

Xincai Ji ◽

Sucharita Saha ◽

Guangping Gao ◽

Amy W. Lasek ◽

Gregg E. Homanics ◽

...

Keyword(s):

Nucleus Accumbens ◽

Sodium Channel ◽

Medium Spiny Neurons ◽

Long Term Depression ◽

Core Nucleus ◽

Auxiliary Subunit ◽

Spiny Neurons

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Cytoarchitectural impairments in the medium spiny neurons of the Nucleus Accumbens core of hyperactive juvenile rats

International Journal of Developmental Neuroscience ◽

10.1016/j.ijdevneu.2010.06.005 ◽

2010 ◽

Vol 28 (6) ◽

pp. 475-480 ◽

Cited By ~ 3

Author(s):

I. González-Burgos ◽

S. García-Martínez ◽

D.A. Velázquez-Zamora ◽

R. Ponce-Rolón

Keyword(s):

Nucleus Accumbens ◽

Medium Spiny Neurons ◽

Nucleus Accumbens Core ◽

Juvenile Rats ◽

Spiny Neurons ◽

Accumbens Core

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Microglial NFκB-TNFα hyperactivation induces obsessive–compulsive behavior in mouse models of progranulin-deficient frontotemporal dementia

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1700477114 ◽

2017 ◽

Vol 114 (19) ◽

pp. 5029-5034 ◽

Cited By ~ 45

Author(s):

Grietje Krabbe ◽

S. Sakura Minami ◽

Jon I. Etchegaray ◽

Praveen Taneja ◽

Biljana Djukic ◽

...

Keyword(s):

Nucleus Accumbens ◽

Frontotemporal Dementia ◽

Knockout Mice ◽

Nuclear Factor Κb ◽

Medium Spiny Neurons ◽

Obsessive Compulsive ◽

Compulsive Disorder ◽

Spiny Neurons ◽

Increased Risk ◽

Excessive Grooming

Frontotemporal dementia (FTD) is the second most common dementia before 65 years of age. Haploinsufficiency in the progranulin (GRN) gene accounts for 10% of all cases of familial FTD. GRN mutation carriers have an increased risk of autoimmune disorders, accompanied by elevated levels of tissue necrosis factor (TNF) α. We examined behavioral alterations related to obsessive–compulsive disorder (OCD) and the role of TNFα and related signaling pathways in FTD patients with GRN mutations and in mice lacking progranulin (PGRN). We found that patients and mice with GRN mutations displayed OCD and self-grooming (an OCD-like behavior in mice), respectively. Furthermore, medium spiny neurons in the nucleus accumbens, an area implicated in development of OCD, display hyperexcitability in PGRN knockout mice. Reducing levels of TNFα in PGRN knockout mice abolished excessive self-grooming and the associated hyperexcitability of medium spiny neurons of the nucleus accumbens. In the brain, PGRN is highly expressed in microglia, which are a major source of TNFα. We therefore deleted PGRN specifically in microglia and found that it was sufficient to induce excessive grooming. Importantly, excessive grooming in these mice was prevented by inactivating nuclear factor κB (NF-κB) in microglia/myeloid cells. Our findings suggest that PGRN deficiency leads to excessive NF-κB activation in microglia and elevated TNFα signaling, which in turn lead to hyperexcitability of medium spiny neurons and OCD-like behavior.

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