Cell-Type-Specific Afferent Innervation of the Nucleus Accumbens Core and Shell
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The nucleus accumbens (NAc) is clearly implicated in reward processing and drug addiction, as well as in numerous neurological and psychiatric disorders; nevertheless, the circuit mechanisms underlying the diverse functions of the NAc remain poorly understood. Here, we characterized the whole-brain and monosynaptic inputs to two main projection cell types - D1 dopamine receptor expressing medium spiny neurons (D1R-MSNs) and D2 dopamine receptor expressing medium spiny neurons (D2R-MSNs) - within the NAc core and NAc shell by rabies-mediated trans-synaptic tracing. We discovered that D1R-MSNs and D2R-MSNs in both NAc subregions receive similar inputs from diverse sources. Inputs to the NAc core are broadly scattered, whereas inputs to the NAc shell are relatively concentrated. Furthermore, we identified numerous brain areas providing important contrasting inputs to different NAc subregions. The anterior cortex preferentially innervates the NAc core for both D1R-MSNs and D2R-MSNs, whereas the lateral hypothalamic area (LH) preferentially targets D1R-MSNs in the NAc shell. Characterizing the cell-type-specific connectivity of different NAc subregions lays a foundation for studying how diverse functions of the NAc are mediated by specific pathways.Keywords:
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Abstract Substance use disorders (SUDs) induce widespread molecular dysregulation in the nucleus accumbens (NAc), a brain region pivotal for coordinating motivation and reward. These molecular changes are thought to support lasting neural and behavioral disturbances that promote drug-seeking in addiction. However, different drug classes exert unique influences on neural circuits, cell types, physiology, and gene expression despite the overlapping symptomatology of SUDs. To better understand common and divergent molecular mechanisms governing SUD pathology, our goal was to survey cell-type-specific restructuring of the NAc transcriptional landscape in after psychostimulant or opioid exposure. We combined fluorescence-activated nuclei sorting and RNA sequencing to profile NAc D1 and D2 medium spiny neurons (MSNs) across cocaine and morphine exposure paradigms, including initial exposure, prolonged withdrawal after repeated exposure, and re-exposure post-withdrawal. Our analyses reveal that D1 MSNs display many convergent transcriptional responses across drug classes during exposure, whereas D2 MSNs manifest mostly divergent responses between cocaine and morphine, with morphine causing more adaptations in this cell type. Utilizing multiscale embedded gene co-expression network analysis (MEGENA), we discerned transcriptional regulatory networks subserving biological functions shared between cocaine and morphine. We observed largely integrative engagement of overlapping gene networks across drug classes in D1 MSNs, but opposite regulation of key D2 networks, highlighting potential therapeutic gene network targets within MSNs. These studies establish a landmark, cell-type-specific atlas of transcriptional regulation induced by cocaine and by morphine that can serve as a foundation for future studies towards mechanistic understanding of SUDs. Our findings, and future work leveraging this dataset, will pave the way for the development of targeted therapeutic interventions, addressing the urgent need for more effective treatments for cocaine use disorder and enhancing the existing strategies for opioid use disorder.
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The present study examined the effect of deep brain stimulation (DBS) in the nucleus accumbens shell on cocaine seeking and neuronal plasticity in rats. Electrical DBS of the accumbens shell attenuated cocaine primed reinstatement across a range of frequencies as low as 12 Hz in male rats. Nucleus accumbens medium spiny neurons (MSNs) can be differentiated by expression of dopamine D1 receptors (D1DRs) or D2DRs. Low-frequency optogenetic-DBS in D1DR- or D2DR-containing neurons attenuated cocaine seeking in male but not female rats. In slice electrophysiology experiments, 12 Hz electrical stimulation evoked long term potentiation (LTP) in D1DR-MSNs and D2DR-MSNs from cocaine naive male and female rats. However, in cocaine-experienced rats, electrical and optical DBS only elicited LTP in D2DR-MSNs from male rats. These results suggest that low frequency DBS in the nucleus accumbens shell effectively, but sex-specifically, suppresses cocaine seeking, which may be associated with the reversal of synaptic plasticity deficits in D2DR-MSNs.
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The nucleus accumbens septi of the normal adult rat was investigated by means of the rapid Golgi impregnation technique according to Valverde (1970). 5 neuron types could be differentiated: type 1: spiny neurons; type 2: few spiny neurons; type 3: aspiny giant neurons; type 4: spiny spindle shaped neurons; type 5: aspiny spidery neurons. The types 1, 4 and 5, resp., are considered, with respect to morphological criteria, to represent interneurons, whereas the types 2 and 3 are considered to be accumbens output neurons. The cytoarchitecture of the nc. accumbens septi thus displays striking similarities with the caudate-putamen-complex. An hypothetical correlation of these neurons in a functional -- biochemical sense as well as their position in the nc. accumbens which is suggested to be a transition area between limbic and extrapyramidal motor systems, is discussed.
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The nucleus accumbens (NAc) is clearly implicated in reward processing and drug addiction, as well as in numerous neurological and psychiatric disorders; nevertheless, the circuit mechanisms underlying the diverse functions of the NAc remain poorly understood. Here, we characterized the whole-brain and monosynaptic inputs to two main projection cell types - D1 dopamine receptor expressing medium spiny neurons (D1R-MSNs) and D2 dopamine receptor expressing medium spiny neurons (D2R-MSNs) - within the NAc core and NAc shell by rabies-mediated trans-synaptic tracing. We discovered that D1R-MSNs and D2R-MSNs in both NAc subregions receive similar inputs from diverse sources. Inputs to the NAc core are broadly scattered, whereas inputs to the NAc shell are relatively concentrated. Furthermore, we identified numerous brain areas providing important contrasting inputs to different NAc subregions. The anterior cortex preferentially innervates the NAc core for both D1R-MSNs and D2R-MSNs, whereas the lateral hypothalamic area (LH) preferentially targets D1R-MSNs in the NAc shell. Characterizing the cell-type-specific connectivity of different NAc subregions lays a foundation for studying how diverse functions of the NAc are mediated by specific pathways.
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Brief dopamine events are critical actors of reward-mediated learning in the striatum; the intracellular cAMP-protein kinase A (PKA) response of striatal medium spiny neurons to such events was studied dynamically using a combination of biosensor imaging in mouse brain slices and in silico simulations. Both D1 and D2 medium spiny neurons can sense brief dopamine transients in the sub-micromolar range. While dopamine transients profoundly change cAMP levels in both types of medium spiny neurons, the PKA-dependent phosphorylation level remains unaffected in D2 neurons. At the level of PKA-dependent phosphorylation, D2 unresponsiveness depends on protein phosphatase-1 (PP1) inhibition by DARPP-32. Simulations suggest that D2 medium spiny neurons could detect transient dips in dopamine level.The phasic release of dopamine in the striatum determines various aspects of reward and action selection, but the dynamics of the dopamine effect on intracellular signalling remains poorly understood. We used genetically encoded FRET biosensors in striatal brain slices to quantify the effect of transient dopamine on cAMP or PKA-dependent phosphorylation levels, and computational modelling to further explore the dynamics of this signalling pathway. Medium-sized spiny neurons (MSNs), which express either D1 or D2 dopamine receptors, responded to dopamine by an increase or a decrease in cAMP, respectively. Transient dopamine showed similar sub-micromolar efficacies on cAMP in both D1 and D2 MSNs, thus challenging the commonly accepted notion that dopamine efficacy is much higher on D2 than on D1 receptors. However, in D2 MSNs, the large decrease in cAMP level triggered by transient dopamine did not translate to a decrease in PKA-dependent phosphorylation level, owing to the efficient inhibition of protein phosphatase 1 by DARPP-32. Simulations further suggested that D2 MSNs can also operate in a 'tone-sensing' mode, allowing them to detect transient dips in basal dopamine. Overall, our results show that D2 MSNs may sense much more complex patterns of dopamine than previously thought.
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