Activating the dorsomedial and ventral midbrain projections to the striatum differentially impairs goal-directed action in male mice

Zou, Simin; Das, Joyosmita; Alexander, Suzanne; Kesby, James P.

doi:10.1016/j.neuropharm.2023.109550

Cited by 3 publications

(2 citation statements)

References 58 publications

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“…What this means for cognition in the EDiPs model remains to be seen. But work in mice has shown that sustained increases in the activity of dorsal striatal dopamine inputs can impair goal-directed behaviour 56 and cognitive flexibility 57 . These impairments are reminiscent of those observed in early and persistent psychosis 58 .…”

Section: Discussionmentioning

confidence: 99%

Increasing dopamine synthesis in nigrostriatal circuits increases phasic dopamine release and alters dorsal striatal connectivity: implications for schizophrenia

Srivastav,

Cui,

Varela

et al. 2023

Schizophr

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One of the most robust neurochemical abnormalities reported in patients with schizophrenia is an increase in dopamine (DA) synthesis and release, restricted to the dorsal striatum (DS). This hyper functionality is strongly associated with psychotic symptoms and progresses in those who later transition to schizophrenia. To understand the implications of this progressive neurobiology on brain function, we have developed a model in rats which we refer to as EDiPs (Enhanced Dopamine in Prodromal schizophrenia). The EDiPs model features a virally mediated increase in dorsal striatal (DS) DA synthesis capacity across puberty and into adulthood. This protocol leads to progressive changes in behaviour and neurochemistry. Our aim in this study was to explore if increased DA synthesis capacity alters the physiology of DA release and DS connectivity. Using fast scan cyclic voltammetry to assess DA release we show that evoked/phasic DA release is increased in the DS of EDiPs rats, whereas tonic/background levels of DA remain unaffected. Using quantitative immunohistochemistry methods to quantify DS synaptic architecture we show a presynaptic marker for DA release sites (Bassoon) was elevated within TH axons specifically within the DS, consistent with the increased phasic DA release in this region. Alongside changes in DA systems, we also show increased density of vesicular glutamate transporter 1 (VGluT1) synapses in the EDiPs DS suggesting changes in cortical connectivity. Our data may prove relevant in understanding the long-term implications for DS function in response to the robust and prolonged increases in DA synthesis uptake and release reported in schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Increasing dopamine synthesis in nigrostriatal circuits increases phasic dopamine release and alters dorsal striatal connectivity: implications for schizophrenia

Srivastav,

Cui,

Varela

et al. 2023

Schizophr

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“…It is also plausible that excessive exercise in ABA is not habitual per se but represents a similar impairment in goal-directed control as seen in the presentation of OCD, where the "goal" is relief of anxiety or negative affect but both the actions (compulsions) and DMS activation (too much) are inappropriate. Since both goal-directed action and motor activity are modulated by dopaminergic transmission Conn, Zou, et al, 2023) using the ABA model could provide mechanistic insight into the relationship between these processes and their relevance to symptoms in AN.…”

Section: Aba Recapitulates An Behavioral Phenotypesmentioning

confidence: 99%

A transdiagnostic and translational framework for delineating the neuronal mechanisms of compulsive exercise in anorexia nervosa

Conn,

Huang,

Gorrell

et al. 2024

Intl J Eating Disorders

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ObjectiveThe development of novel treatments for anorexia nervosa (AN) requires a detailed understanding of the biological underpinnings of specific, commonly occurring symptoms, including compulsive exercise. There is considerable bio‐behavioral overlap between AN and obsessive‐compulsive disorder (OCD), therefore it is plausible that similar mechanisms underlie compulsive behavior in both populations. While the association between these conditions is widely acknowledged, defining the shared mechanisms for compulsive behavior in AN and OCD requires a novel approach.MethodsWe present an argument that a better understanding of the neurobiological mechanisms that underpin compulsive exercise in AN can be achieved in two critical ways. First, by applying a framework of the neuronal control of OCD to exercise behavior in AN, and second, by taking better advantage of the activity‐based anorexia (ABA) rodent model to directly test this framework in the context of feeding pathology.ResultsA cross‐disciplinary approach that spans preclinical, neuroimaging, and clinical research as well as compulsive neurocircuitry and behavior can advance our understanding of when, why, and how compulsive exercise develops in the context of AN and provide targets for novel treatment strategies.DiscussionIn this article, we (i) link the expression of compulsive behavior in AN and OCD via a transition between goal‐directed and habitual behavior, (ii) present disrupted cortico‐striatal circuitry as a key substrate for the development of compulsive behavior in both conditions, and (iii) highlight the utility of the ABA rodent model to better understand the mechanisms of compulsive behavior relevant to AN.Public SignificanceIndividuals with AN who exercise compulsively are at risk of worse health outcomes and have poorer responses to standard treatments. However, when, why, and how compulsive exercise develops in AN remains inadequately understood. Identifying whether the neural circuitry underlying compulsive behavior in OCD also controls hyperactivity in the activity‐based anorexia model will aid in the development of novel eating disorder treatment strategies for this high‐risk population.

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Antagonism of D2 receptors via raclopride ameliorates amphetamine-induced associative learning deficits in male mice

Conn,

Alexander,

Burne

et al. 2023

Behavioural Brain Research

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Activating the dorsomedial and ventral midbrain projections to the striatum differentially impairs goal-directed action in male mice

Cited by 3 publications

References 58 publications

Increasing dopamine synthesis in nigrostriatal circuits increases phasic dopamine release and alters dorsal striatal connectivity: implications for schizophrenia

Increasing dopamine synthesis in nigrostriatal circuits increases phasic dopamine release and alters dorsal striatal connectivity: implications for schizophrenia

A transdiagnostic and translational framework for delineating the neuronal mechanisms of compulsive exercise in anorexia nervosa

Antagonism of D2 receptors via raclopride ameliorates amphetamine-induced associative learning deficits in male mice

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