A novel multidimensional reinforcement task in mice elucidates sex-specific behavioral strategies

Kutlu, Munir Gunes; Zachry, Jennifer E.; Brady, Lillian J.; Melugin, Patrick R.; Sanders, Christina; Tat, Jimmy; Johnson, Amy; Thibeault, Kimberly C.; López, Alberto J.; Calipari, Erin S.

doi:10.1101/690750

Cited by 6 publications

(18 citation statements)

References 34 publications

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“…It is likely that differences in protein expression at baseline interact with drug actions on reward systems to alter druginduced molecular plasticity and may provide a framework that can explain sex differences in both vulnerability and the trajectory of SUD. Understanding the interaction between these factors is particularly relevant as significant work has suggested that males and females have different behavioral strategies, especially as it relates to reward and reinforcement behavior 12 . These sexspecific behavioral strategies have been largely linked to rewardrelated brain regions like the nucleus accumbens (NAc), where manipulations of this area (either directly or via manipulations of projections into the NAc) are capable of blocking/inducing these differences in behavior [12][13][14] .…”

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confidence: 99%

“…Understanding the interaction between these factors is particularly relevant as significant work has suggested that males and females have different behavioral strategies, especially as it relates to reward and reinforcement behavior 12 . These sexspecific behavioral strategies have been largely linked to rewardrelated brain regions like the nucleus accumbens (NAc), where manipulations of this area (either directly or via manipulations of projections into the NAc) are capable of blocking/inducing these differences in behavior [12][13][14] . Thus, a major goal of this study was to focus on basal sex differences in motivation and protein expression in the NAc, and how these interact with cocaine selfadministration to dictate the molecular and behavioral adaptations that occur following cocaine exposure.…”

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confidence: 99%

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Cocaine self-administration induces sex-dependent protein expression in the nucleus accumbens

et al. 2021

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Substance use disorder (SUD) is a chronic neuropsychiatric condition characterized by long-lasting alterations in the neural circuitry regulating reward and motivation. Substantial work has focused on characterizing the molecular substrates that underlie these persistent changes in neural function and behavior. However, this work has overwhelmingly focused on male subjects, despite mounting clinical and preclinical evidence that females demonstrate dissimilar progression to SUD and responsivity to stimulant drugs of abuse, such as cocaine. Here, we show that sex is a critical biological variable that defines drug-induced plasticity in the nucleus accumbens (NAc). Using quantitative mass spectrometry, we assessed the protein expression patterns induced by cocaine self-administration and demonstrated unique molecular profiles between males and females. We show that 1. Cocaine self-administration induces non-overlapping protein expression patterns in significantly regulated proteins in males and females and 2. Critically, cocaine-induced protein regulation differentially interacts with sex to eliminate basal sexual dimorphisms in the proteome. Finally, eliminating these baseline differences in the proteome is concomitant with the elimination of sex differences in behavior for non-drug rewards. Together, these data suggest that cocaine administration is capable of rewriting basal proteomic function and reward-associated behaviors.

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Cocaine self-administration induces sex-dependent protein expression in the nucleus accumbens

et al. 2021

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“…This is problematic as it not only selects for male-type behavioral profiles but can also mask sex-differences in subsequent drug-associated behaviors. Several studies have demonstrated that female and male mice employ unique behavioral strategies in operant reinforcement tasks [61]. As such, if sex is to be accurately considered as a biological variable in behavioral, circuit, and molecular analyses, training paradigms and selection criteria should be able to parse volitional intake while taking into account baseline behavioral differences between male and female subjects.…”

Section: Discussionmentioning

confidence: 99%

“…Each statistical test is denoted with the appropriate statistics in the results section. We also used a computational analysis to determine the parameters of response bias (Log b), as described previously [36][37][38]. Briefly, Log b was computed as the measure for behavioral bias using a logarithmic scale for the multiplication of the ratio between correct and incorrect responses:…”

Section: Analysis Parametersmentioning

confidence: 99%

An optimized procedure for robust volitional drug intake in mice

et al. 2019

Preprint

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Substance use disorder is a behavioral disorder characterized by volitional drug consumption, compulsive behavior, drug seeking, and relapse. Mouse models of substance use disorder allow for the use of molecular, genetic, and circuit level tools, which provide enormous potential for defining the underlying mechanisms of this disorder. However, the relevance of results depends entirely on the validity of the mouse models used. Self-administration models have long been considered the gold standard of preclinical addiction models, as they allow for volitional drug use, this providing strong face validity. In a series of experiments, we show that traditional mouse models of self-administration, where behavior is maintained on a fixed-ratio one schedule of reinforcement, show similar levels of responding in the presence and absence of drug delivery -demonstrating that it is impossible to determine when intake is and is not volitional. Further, when assessing inclusion criteria, we find a sex-bias in exclusion criteria where females that acquired food self-administration were eliminated when traditional criteria were applied. To address these issues, we have developed a novel mouse self-administration procedure where animals do not need to be pre-trained on food and behavior is maintained on a variable ratio schedule of reinforcement. This procedure increases rates of reinforcement behavior, increases levels of drug intake, and eliminates sex bias in inclusion criteria. Together, these data highlight a major issue with fixed-ratio models in mice that complicates subsequent analysis and provide a simple and novel approach to minimize these confounds with escalating variable-ratio schedules of reinforcement.

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“…Studies to explicitly test whether the reviewed mechanisms are present in females, the microcircuits are organized the same way between the sexes, or whether they affect dopamine release to a similar extent in both sexes have not been completed to date. Furthermore, while work has focused on how sex interacts with aspects of substance use (Siciliano, 2019; Townsend, Negus, Caine, Thomsen, & Banks, 2019), depression (Ma, Xu, Wang, & Li, 2019), motivation, and the dopaminergic mechanisms underlying these phenotypes (Becker & Koob, 2016; Johson et al, 2019; Kutlu et al, 2020), it remains mostly unclear how sex interacts with the specific local terminal regulatory mechanisms outlined in this review to drive these behaviors. Taken together, lack of understanding of how terminal dopamine is modulated in both males and females will further impede the development of pharmaceuticals to many neuropsychiatric conditions involving dopamine dysfunction, including substance use disorder (Correa‐De‐Araujo, 2006).…”

Section: Expanding Our Understanding Of Dopamine Release Regulationmentioning

confidence: 99%

Direct dopamine terminal regulation by local striatal microcircuitry

Nolan

Zachry

Johnson

et al. 2020

Journal of Neurochemistry

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Regulation of axonal dopamine release by local microcircuitry is at the hub of several biological processes that govern the timing and magnitude of signaling events in reward-related brain regions. An important characteristic of dopamine release from axon terminals in the striatum is that it is rapidly modulated by local regulatory mechanisms. These processes can occur via homosynaptic mechanisms-such How to cite this article: NolanSO, Zachry JF, Johnson AR,

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A novel multidimensional reinforcement task in mice elucidates sex-specific behavioral strategies

Cited by 6 publications

References 34 publications

Cocaine self-administration induces sex-dependent protein expression in the nucleus accumbens

Cocaine self-administration induces sex-dependent protein expression in the nucleus accumbens

An optimized procedure for robust volitional drug intake in mice

Direct dopamine terminal regulation by local striatal microcircuitry

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