Cocaine place conditioning strengthens location-specific hippocampal inputs to the nucleus accumbens

Conditioned place preference (CPP) is a widely used model of addiction-related behavior whose underlying mechanism is not understood. In this study, we used dual site silicon probe recordings in freely moving mice to examine interactions between the hippocampus and nucleus accumbens in cocaine CPP. We found that CPP was associated with recruitment of nucleus accumbens medium spiny neurons to fire in the cocaine-paired location, and this recruitment was driven predominantly by selective strengthening of hippocampal inputs arising from place cells that encode the cocaine-paired location. These findings provide in vivo evidence that the synaptic potentiation in the accumbens caused by repeated cocaine administration preferentially affects inputs that were active at the time of drug exposure. This provides a potential physiological mechanism by which drug use becomes associated with specific environmental contexts.

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Binge Alcohol Drinking Alters Synaptic Processing of Executive and Emotional Information in Core Nucleus Accumbens Medium Spiny Neurons

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.742207 ◽

2021 ◽

Vol 15 ◽

Author(s):

Jenya Kolpakova ◽

Vincent van der Vinne ◽

Pablo Giménez-Gómez ◽

Timmy Le ◽

In-Jee You ◽

...

Keyword(s):

Nucleus Accumbens ◽

Alcohol Drinking ◽

Drugs Of Abuse ◽

Alcohol Exposure ◽

Medium Spiny Neurons ◽

Dependent Manner ◽

Emotional Information ◽

Core Nucleus ◽

Spiny Neurons

The nucleus accumbens (NAc) is a forebrain region mediating the positive-reinforcing properties of drugs of abuse, including alcohol. It receives glutamatergic projections from multiple forebrain and limbic regions such as the prefrontal cortex (PFCx) and basolateral amygdala (BLA), respectively. However, it is unknown how NAc medium spiny neurons (MSNs) integrate PFCx and BLA inputs, and how this integration is affected by alcohol exposure. Because progress has been hampered by the inability to independently stimulate different pathways, we implemented a dual wavelength optogenetic approach to selectively and independently stimulate PFCx and BLA NAc inputs within the same brain slice. This approach functionally demonstrates that PFCx and BLA inputs synapse onto the same MSNs where they reciprocally inhibit each other pre-synaptically in a strict time-dependent manner. In alcohol-naïve mice, this temporal gating of BLA-inputs by PFCx afferents is stronger than the reverse, revealing that MSNs prioritize high-order executive processes information from the PFCx. Importantly, binge alcohol drinking alters this reciprocal inhibition by unilaterally strengthening BLA inhibition of PFCx inputs. In line with this observation, we demonstrate that in vivo optogenetic stimulation of the BLA, but not PFCx, blocks binge alcohol drinking escalation in mice. Overall, our results identify NAc MSNs as a key integrator of executive and emotional information and show that this integration is dysregulated during binge alcohol drinking.

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Error-related Signaling in Nucleus Accumbens D2 Receptor-expressing Neurons Guides Avoidance-based Goal-directed Behavior

10.21203/rs.3.rs-1109714/v1 ◽

2022 ◽

Author(s):

Tadaaki Nishioka ◽

Tom Macpherson ◽

Kosuke Hamaguchi ◽

Takatoshi Hikida

Keyword(s):

Nucleus Accumbens ◽

Behavioral Control ◽

D2 Receptor ◽

Environmental Cues ◽

Medium Spiny Neurons ◽

Spiny Neurons ◽

Cell Type Specific ◽

Goal Directed Behavior

Abstract Learnt associations between environmental cues and the outcomes they predict (cue-outcome associations) play a major role in behavioral control, guiding not only which responses we should perform, but also which we should avoid, in order to achieve a specific goal. The encoding of such cue-outcome associations, as well as the performance of cue-guided goal-directed behavior, is thought to involve dopamine D1 and D2 receptor-expressing medium spiny neurons (D1-/D2-MSNs) of the nucleus accumbens (NAc). Here, using a visual discrimination task in mice, we assessed the role of NAc D1-/D2-MSNs in cue-guided goal-directed avoidance of inappropriate responding. Cell-type specific neuronal silencing and in-vivo imaging revealed NAc D2-MSNs to selectively contribute to cue-guided avoidance behavior, with activation of NAc D2-MSNs following response error playing an important role in optimizing future goal-directed behavior. Our findings indicate that error-signaling by NAc D2-MSNs underlies the ability to use environmental cues to avoid inappropriate behavior.

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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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Sex-Specific Role for Egr3 in Nucleus Accumbens D2-Medium Spiny Neurons Following Long-Term Abstinence From Cocaine Self-administration

Biological Psychiatry ◽

10.1016/j.biopsych.2019.10.019 ◽

2020 ◽

Vol 87 (11) ◽

pp. 992-1000 ◽

Cited By ~ 6

Author(s):

Michel Engeln ◽

Swarup Mitra ◽

Ramesh Chandra ◽

Utsav Gyawali ◽

Megan E. Fox ◽

...

Keyword(s):

Nucleus Accumbens ◽

Specific Role ◽

Medium Spiny Neurons ◽

Self Administration ◽

Spiny Neurons

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Trafficking of calcium-permeable and calcium-impermeable AMPA receptors in nucleus accumbens medium spiny neurons co-cultured with prefrontal cortex neurons

Neuropharmacology ◽

10.1016/j.neuropharm.2016.12.014 ◽

2017 ◽

Vol 116 ◽

pp. 224-232 ◽

Cited By ~ 5

Author(s):

Craig T. Werner ◽

Conor H. Murray ◽

Jeremy M. Reimers ◽

Niravkumar M. Chauhan ◽

Kenneth K.Y. Woo ◽

...

Keyword(s):

Prefrontal Cortex ◽

Nucleus Accumbens ◽

Ampa Receptors ◽

Medium Spiny Neurons ◽

Spiny Neurons

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Presence of Inhibitory Glycinergic Transmission in Medium Spiny Neurons in the Nucleus Accumbens

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2018.00228 ◽

2018 ◽

Vol 11 ◽

Cited By ~ 6

Author(s):

Braulio Muñoz ◽

Gonzalo E. Yevenes ◽

Benjamin Förstera ◽

David M. Lovinger ◽

Luis G. Aguayo

Keyword(s):

Nucleus Accumbens ◽

Medium Spiny Neurons ◽

Spiny Neurons

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Pitx3 Deficiency in Mice Affects Cholinergic Modulation of GABAergic Synapses in the Nucleus Accumbens

Journal of Neurophysiology ◽

10.1152/jn.00333.2006 ◽

2006 ◽

Vol 96 (4) ◽

pp. 2034-2041 ◽

Cited By ~ 2

Author(s):

Mischa de Rover ◽

Johannes C. Lodder ◽

Marten P. Smidt ◽

Arjen B. Brussaard

Keyword(s):

Nucleus Accumbens ◽

Medium Spiny Neurons ◽

Wild Type ◽

Cholinergic Modulation ◽

Firing Patterns ◽

Neural Adaptations ◽

Cholinergic Interneurons ◽

Spiny Neurons ◽

Gating Mechanism ◽

Deficient Mice

We investigated to what extent Pitx3 deficiency, causing hyperdopaminergic transmission in the nucleus accumbens microcircuitry, may lead to developmental changes. First, spontaneous firing activity of cholinergic interneurons in the nucleus accumbens was recorded in vitro. Firing patterns in the Pitx3-deficient mice were more variable and intrinsically different from those observed in wild-type mice. Next, to test whether the irregular firing patterns observed in mutant mice affected the endogenous nicotinic modulation of the GABAergic input of medium spiny neurons, we recorded spontaneous GABAergic inputs to these cells before and after the application of the nicotinic receptor blocker mecamylamine. Effects of mecamylamine were found in slices of either genotype, but in a rather inconsistent manner. Possibly this was attributable to heterogeneity in firing of nearby cholinergic interneurons. Thus paired recordings of cholinergic interneurons and medium spiny neurons were performed to more precisely control the experimental conditions of the cholinergic modulation of GABAergic synaptic transmission. We found that controlling action potential firing in cholinergic neurons leads to a conditional increase in GABAergic input frequency in wild-type mice but not in Pitx3-deficient mice. We conclude that Pitx3-deficient mice have neural adaptations at the level of the nucleus accumbens microcircuitry that in turn may have behavioral consequences. It is discussed to what extent dopamine release in the nucleus accumbens may be a long-term gating mechanism leading to alterations in cholinergic transmission in the nucleus accumbens, in line with previously reported neural adaptations found as consequences of repeated drug treatment in rodents.

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