Duration- and sex-dependent neural circuit control of voluntary physical activity

Tanner, Margaret K.; Davis, Jazmyne K.P.; Jaime, Jennifer; Moya, Nicolette A; Hohorst, Alyssa A.; Bonar, Kelsey; Abrams, Kelsey A.; Jamil, Nashra; Han, Rebecca; Hubert, Troy; Brown, Nadja; Loetz, Esteban C.; Greenwood, Benjamin N.

doi:10.1007/s00213-022-06243-0

Cited by 10 publications

(10 citation statements)

References 77 publications

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“…To determine whether neural activity within unique DS subregions is necessary for normal fear extinction, a cocktail of the GABA A /GABA B receptor agonists Musc/Bac was injected directly into the DMS or DLS prior to fear extinction. Increasing confidence that Musc/Bac can successfully inhibit neural activity in DS subregions is the observation that the same Musc/Bac cocktail as used here inhibits neural activity in the DMS and DLS elicited by a bout of voluntary wheel running [36]. Similar to prior reports [36], neither DMS nor DLS inhibition altered general locomotor activity (Figures 3F and 3L).…”

Section: Discussionsupporting

confidence: 84%

“…Microinjectors were left in place for 2 min after infusion to allow for diffusion. Microinjections occurred 15 min prior to fear extinction training, as this was the timepoint used in our prior studies using these drugs [32, 36]. All rats were exposed to mock infusion procedures in the infusion room once a day for 2 days prior to microinjections to habituate rats to the microinjection procedure.…”

Section: Methodsmentioning

confidence: 99%

“…Bilateral 26-gauge guide cannulae (Plastics One, Roanoke, VA, USA) were targeted to either the DMS (+0.5 mm anterior, ± 1.8 mm lateral, − 4.6 mm ventral from the top of the skull) or DLS (+0.5 mm anterior, ± 4.2 mm lateral, − 4.9 mm ventral from the top of the skull) according to the Paxinos and Watson rat brain atlas [35] and our recent work [36]. All surgeries were performed under ketamine (75.0 mg/kg i.p.)…”

Section: Stereotaxic Surgerymentioning

confidence: 99%

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Pharmacological manipulations of the dorsomedial and dorsolateral striatum during fear extinction have opposing effects on fear renewal

Tanner,

Hohorst,

Westerman

et al. 2024

Preprint

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Systemic manipulations that enhance dopamine (DA) transmission around the time of fear extinction can strengthen fear extinction and reduce conditioned fear relapse. Prior studies investigating the brain regions where DA augments fear extinction focus on targets of mesolimbic and mesocortical DA systems originating in the ventral tegmental area, given the role of these DA neurons in prediction error. The dorsal striatum (DS), a primary target of the nigrostriatal DA system originating in the substantia nigra (SN), is implicated in behaviors beyond its canonical role in movement, such as reward and punishment, goal-directed action, and stimulus-response associations, but whether DS DA contributes to fear extinction is unknown. We have observed that chemogenetic stimulation of SN DA neurons during fear extinction prevents the return of fear in contexts different from the extinction context, a form of relapse called renewal. This effect of SN DA stimulation is mimicked by a DA D1 receptor (D1R) agonist injected into the DS, thus implicating DS DA in fear extinction. Different DS subregions subserve unique functions of the DS, but it is unclear where in the DS D1R agonist acts during fear extinction to reduce renewal. Furthermore, although fear extinction increases neural activity in DS subregions, whether neural activity in DS subregions is causally involved in fear extinction is unknown. To explore the role of DS subregions in fear extinction, adult, male Long-Evans rats received microinjections of either the D1R agonist SKF38393 or a cocktail consisting of GABAA/GABAB receptor agonists muscimol/baclofen selectively into either dorsomedial (DMS) or dorsolateral (DLS) DS subregions immediately prior to fear extinction, and extinction retention and renewal were subsequently assessed drug-free. While increasing D1R signaling in the DMS during fear extinction did not impact fear extinction retention or renewal, DMS inactivation reduced later renewal. In contrast, DLS inactivation had no effect on fear extinction retention or renewal but increasing D1R signaling in the DLS during extinction reduced fear renewal. These data suggest that DMS and DLS activity during fear extinction can have opposing effects on later fear renewal, with the DMS promoting renewal and the DLS opposing renewal. Mechanisms through which the DS could influence the contextual gating of fear extinction are discussed.

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Section: Discussionsupporting

confidence: 84%

Section: Methodsmentioning

confidence: 99%

Section: Stereotaxic Surgerymentioning

confidence: 99%

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Pharmacological manipulations of the dorsomedial and dorsolateral striatum during fear extinction have opposing effects on fear renewal

Tanner,

Hohorst,

Westerman

et al. 2024

Preprint

Self Cite

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show abstract

“…When motivation for reward is absent, the dorsal striatum emerges as the prevailing circuit with a bias toward habit formation, and with changes in relative synaptic strength arising in the DMS vs. DLS due to the DAT Val559 mutation. Emerging evidence suggests that engagement of striatal circuitry during operant learning differs by sex [ 66 ]. Intriguingly, the impacts of ADE in DAT Val559 mice also differ in a sex- and region-specific manner with DAT Val559 females displaying alterations in DA dynamics specific to the ventral striatum [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Male DAT Val559 Mice Exhibit Compulsive Behavior under Devalued Reward Conditions Accompanied by Cellular and Pharmacological Changes

Stewart

Davis

Areal

et al. 2022

Cells

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Identified across multiple psychiatric disorders, the dopamine (DA) transporter (DAT) Ala559Val substitution triggers non-vesicular, anomalous DA efflux (ADE), perturbing DA neurotransmission and behavior. We have shown that DAT Val559 mice display a waiting impulsivity and changes in cognitive performance associated with enhanced reward motivation. Here, utilizing a within-subject, lever-pressing paradigm designed to bias the formation of goal-directed or habitual behavior, we demonstrate that DAT Val559 mice modulate their nose poke behavior appropriately to match context, but demonstrate a perseverative checking behavior. Although DAT Val559 mice display no issues with the cognitive flexibility required to acquire and re-learn a visual pairwise discrimination task, devaluation of reward evoked habitual reward seeking in DAT Val559 mutants in operant tasks regardless of reinforcement schedule. The direct DA agonist apomorphine also elicits locomotor stereotypies in DAT Val559, but not WT mice. Our observation that dendritic spine density is increased in the dorsal medial striatum (DMS) of DAT Val559 mice speaks to an imbalance in striatal circuitry that might underlie the propensity of DAT Val559 mutants to exhibit compulsive behaviors when reward is devalued. Thus, DAT Val559 mice represent a model for dissection of how altered DA signaling perturbs circuits that normally balance habitual and goal-directed behaviors.

show abstract

“…When motivation for reward is absent, the dorsal striatum emerges as the prevailing circuit with a bias toward habit formation, and with changes in relative synaptic strength arising in the DMS vs DLS due to the DAT Val559 mutation. Emerging evidence suggests that engagement of striatal circuitry during operant learning differs by sex[65]. Intriguingly, the impacts of ADE in DAT Val559 mice also differ in a sex- and region-specific manner with DAT Val559 females displaying alterations in DA dynamics specific to the ventral striatum[45].…”

Section: Discussionmentioning

confidence: 99%

DAT Val559 Mice Exhibit Compulsive Behavior Under Devalued Reward Conditions Accompanied by Cellular and Pharmacological Changes

Stewart

Davis

Areal

et al. 2022

Preprint

View full text Add to dashboard Cite

Identified across multiple psychiatric disorders, the dopamine (DA) transporter (DAT) Ala559Val substitution triggers non-vesicular, anomalous DA efflux (ADE), perturbing DA neurotransmission and behavior. We have shown that DAT Val559 mice display a waiting impulsivity and changes in cognitive performance associated with enhanced reward motivation. Here, utilizing a within-subject, lever-pressing paradigm designed to bias the formation of goal-directed or habitual behavior, we demonstrate that DAT Val559 mice modulate their nose-poke behavior appropriately to match context, but demonstrate a perseverative checking behavior. Although DAT Val559 mice display no issues with the cognitive flexibility required to acquire and re-learn a visual pair-wise discrimination task, devaluation of reward evoked habitual reward seeking in DAT Val559 mutants in operant tasks regardless of reinforcement schedule. The direct DA agonist apomorphine also elicits locomotor stereotypies in DAT Val559, but not WT mice. Our observation that dendritic spine density is increased in the dorsal medial striatum (DMS) of DAT Val559 mice speaks to an imbalance in striatal circuitry that might underlie the propensity of DAT Val559 mutants to exhibit compulsive behaviors when reward is devalued. Thus, DAT Val559 mice represent a model for dissection of how altered DA signaling perturbs circuits that normally balance habitual and goal-directed behaviors.

show abstract

Duration- and sex-dependent neural circuit control of voluntary physical activity

Cited by 10 publications

References 77 publications

Pharmacological manipulations of the dorsomedial and dorsolateral striatum during fear extinction have opposing effects on fear renewal

Pharmacological manipulations of the dorsomedial and dorsolateral striatum during fear extinction have opposing effects on fear renewal

Male DAT Val559 Mice Exhibit Compulsive Behavior under Devalued Reward Conditions Accompanied by Cellular and Pharmacological Changes

DAT Val559 Mice Exhibit Compulsive Behavior Under Devalued Reward Conditions Accompanied by Cellular and Pharmacological Changes

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