Selective chemogenetic inactivation of corticoaccumbal projections disrupts trait choice impulsivity

Wenzel, Jennifer M.; Zlebnik, Natalie E.; Patton, Mary H.; Smethells, John R.; Ayvazian, Victoria M.; Dantrassy, Hannah M.; Zhang, Lan-Yuan; Mathur, Brian N.; Cheer, Joseph F.

doi:10.1038/s41386-023-01604-5

Cited by 6 publications

(11 citation statements)

References 149 publications

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“…ISD disrupts delay-discounting behavior, and its effects depend on the basal levels of impulsivity. As previously reported by others 32 , 33 , 46 , we found that rats can be grouped in low impulsive and high impulsive according to their basal preference for LR choices. In low impulsive animals, ISD decreased the number of LR lever presses with higher delays (10 and 20 s) compared to controls, which suggests that ISD increases choice impulsivity.…”

Section: Discussionsupporting

confidence: 87%

“…increases choice impulsivity). Furthermore, electrophysiological and pharmacogenetic studies demonstrate that specific neuronal populations in the mPFC regulate delay discounting behavior 32 , 33 . In particular, a recent study shows that the inhibition of mPFC neuronal projections to nucleus accumbens increases choice impulsivity in rats, and that this effect depends on individuals’ basal levels of impulsivity 33 .…”

Section: Introductionmentioning

confidence: 99%

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Choice impulsivity after repeated social stress is associated with increased perineuronal nets in the medial prefrontal cortex

Martinez,

Pantazopoulos,

Gisabella

et al. 2024

Sci Rep

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Repeated stress can predispose to substance abuse. However, behavioral and neurobiological adaptations that link stress to substance abuse remain unclear. This study investigates whether intermittent social defeat (ISD), a stress protocol that promotes drug-seeking behavior, alters intertemporal decision-making and cortical inhibitory function in the medial prefrontal cortex (mPFC). Male long evans rats were trained in a delay discounting task (DDT) where rats make a choice between a fast (1 s) small reward (1 sugar pellet) and a large reward (3 sugar pellets) that comes with a time delay (10 s or 20 s). A decreased preference for delayed rewards was used as an index of choice impulsivity. Rats were exposed to ISD and tested in the DDT 24 h after each stress episode, and one- and two-weeks after the last stress episode. Immunohistochemistry was performed in rat’s brains to evaluate perineuronal nets (PNNs) and parvalbumin GABA interneurons (PV) labeling as markers of inhibitory function in mPFC. ISD significantly decreased the preference for delayed large rewards in low impulsive, but not high impulsive, animals. ISD also increased the density of PNNs in the mPFC. These results suggest that increased choice impulsivity and cortical inhibition predispose animals to seek out rewards after stress.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Choice impulsivity after repeated social stress is associated with increased perineuronal nets in the medial prefrontal cortex

Martinez,

Pantazopoulos,

Gisabella

et al. 2024

Sci Rep

View full text Add to dashboard Cite

show abstract

“…As previously reported by others 31,32,42 , we found that rats can be grouped in low impulsive and high impulsive according to their basal preference for LR choices. In low impulsive animals, ISD decreased the number of LR lever presses with higher delays (10 and 20 s) compared to controls, which suggests that ISD increases choice impulsivity.…”

Section: Discusionsupporting

confidence: 85%

“…In line with these studies, the higher density of PNNs shown here suggests that an increased cortical inhibitory activity in the mPFC contributes to enhance choice impulsivity after ISD. A very recent study demonstrates that the inhibition of mPFC-nucleus accumbens projections increases choice impulsivity in a delay discounting task 32 . Based on this evidence, it is possible that ISD increases choice impulsivity by enhancing the inhibition over mPFC-nucleus accumbens projections.…”

Section: Discusionmentioning

confidence: 99%

Choice impulsivity after repeated social stress is associated with increased perineuronal nets in the medial prefrontal cortex

Martinez,

Pantazopoulos,

Gisabella

et al. 2024

Preprint

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Repeated stress can predispose to substance abuse. However, behavioral and neurobiological adaptations that link stress to substance abuse remain unclear. This study investigates whether Intermittent Social Defeat (ISD), a stress protocol that promotes drug-seeking behavior, alters intertemporal decision-making and cortical inhibitory function in the medial prefrontal cortex (mPFC). Male Long Evans rats were trained in a delay discounting task (DDT) where rats make a choice between a fast (1s) small reward (1 sugar pellet) and a large (3 sugar pellets) reward that comes with a time delay (10 or 20s). A decreased preference for delayed rewards was used as an index of choice impulsivity. Rats were exposed to ISD and tested in DDT 24 hours after each stress episode, and one-and two-weeks after the last stress episode. Immunohistochemistry was performed in rats brains to evaluate perineuronal nets (PNNs) and parvalbumin GABA interneurons (PV) labeling as markers of inhibitory function in the mPFC. In the DDT, ISD significantly decreased the preference for delayed large rewards, in the short and long term. ISD also increased the density of PNNs in the mPFC. These results suggest that increased choice impulsivity and cortical inhibition predispose animals to seek out rewards after stress.

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“…The increase in K (a steeper discounting curve), suggested PPX-treated animals more heavily weighted the cost of delay. We also quantified the shape of the discounting curve by measuring area-under-the-curve (AUC); in this analysis, a decrease in AUC indicated an in increase in impulsive choice (41, 42). PPX treatment led to a significant reduction in AUC in parkinsonian mice, suggesting that PPX shifted choices towards immediate/small rewards at all delays (Fig.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Indirect Pathway Activity Causes Abnormal Decision-Making In a Mouse Model of Impulse Control Disorder in Parkinson’s Disease

Zhuang,

Lemak,

Sridhar

et al. 2024

Preprint

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Healthy action selection relies on the coordinated activity of striatal direct and indirect pathway neurons. In Parkinson’s disease (PD), in which loss of midbrain dopamine neurons is associated with progressive motor and cognitive deficits, this coordination is disrupted. Dopamine replacement therapy can remediate motor symptoms, but can also cause impulse control disorder (ICD), which is characterized by pathological gambling, hypersexuality, and/or compulsive shopping. The cellular and circuit mechanisms of ICD remain unknown. Here we developed a mouse model of PD/ICD, in which ICD-like behavior was assayed with a delay discounting task. We found that in parkinsonian mice, the dopamine agonist pramipexole drove more pronounced delay discounting, as well as disrupted firing in both direct and indirect pathway neurons. We found that chemogenetic inhibition of indirect pathway neurons in parkinsonian mice drove similar phenotypes. Together, these findings provide a new mouse model and insights into ICD pathophysiology.

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Selective chemogenetic inactivation of corticoaccumbal projections disrupts trait choice impulsivity

Cited by 6 publications

References 149 publications

Choice impulsivity after repeated social stress is associated with increased perineuronal nets in the medial prefrontal cortex

Choice impulsivity after repeated social stress is associated with increased perineuronal nets in the medial prefrontal cortex

Choice impulsivity after repeated social stress is associated with increased perineuronal nets in the medial prefrontal cortex

Inhibition of Indirect Pathway Activity Causes Abnormal Decision-Making In a Mouse Model of Impulse Control Disorder in Parkinson’s Disease

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