Regulation of risky decision making by gonadal hormones in males and females

Orsini, Caitlin A.; Blaes, Shelby L; Hernandez, Caesar M; Betzhold, Sara M; Perera, Hassan; Wheeler, Alexa-Rae; Eyck, Tyler W Ten; Garman, Tyler S.; Bizon, Jennifer L.; Setlow, Barry

doi:10.1038/s41386-020-00827-0

Cited by 32 publications

(29 citation statements)

References 76 publications

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“…to regulate aspects of value-based decision making in female rats (Uban et al, 2012;Orsini et al, 2021), including explore/exploit balance (Verharen et al, 2019b). These data suggest that the rise in ovarian hormones at puberty could contribute to the developmental shift in choice policy during adolescence in females.…”

Section: Introductionmentioning

confidence: 81%

“…In humans, choice behavior generally becomes less exploratory and more exploitative during the transition from childhood to adulthood (Nussenbaum and Hartley, 2019; Gopnik, 2020; Xia et al, 2020; Eckstein et al, 2021). Natural fluctuations in ovarian hormones across the estrous cycle or exogenous estradiol administration have been shown to regulate aspects of value-based decision making in female rats (Uban et al, 2012; Orsini et al, 2021), including explore/exploit balance (Verharen et al, 2019b). These data suggest that the rise in ovarian hormones at puberty could contribute to the developmental shift in choice policy during adolescence in females.…”

Section: Introductionmentioning

confidence: 99%

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Prepubertal ovariectomy alters dorsomedial striatum indirect pathway neuron excitability and explore/exploit balance in female mice

Delevich

Wilbrecht

2021

Preprint

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Decision-making circuits are modulated across life stages (e.g. juvenile, adolescent, or adult)—as well as on the shorter timescale of reproductive cycles in females—to meet changing environmental and physiological demands. Ovarian hormonal modulation of relevant neural circuits is a potential mechanism by which behavioral flexibility is regulated in females. Here we examined the influence of prepubertal ovariectomy (pOVX) versus sham surgery on performance in an odor-based multiple choice reversal task. We observed that pOVX females made different types of errors during reversal learning compared to sham surgery controls. Using reinforcement learning models fit to trial-by-trial behavior, we found that pOVX females exhibited lower inverse temperature parameter (β) compared to sham females. These findings suggest that OVX females solve the reversal task using a more exploratory choice policy, whereas sham females use a more exploitative policy prioritizing estimated high value options. To seek a neural correlate of this behavioral difference, we performed whole-cell patch clamp recordings within the dorsomedial striatum (DMS), a region implicated in regulating action selection and explore/exploit choice policy. We found that the intrinsic excitability of dopamine receptor type 2 (D2R) expressing indirect pathway spiny projection neurons (iSPNs) was significantly higher in pOVX females compared to both unmanipulated and sham surgery females. Finally, to test whether mimicking this increase in iSPN excitability could recapitulate the pattern of reversal task behavior observed in pOVX females, we chemogenetically activated DMS D2R(+) neurons within intact female mice. We found that chemogenetic activation increased exploratory choice during reversal, similar to the pattern we observed in pOVX females. Together, these data suggest that pubertal status may influence explore/exploit balance in females via the modulation of iSPN intrinsic excitability within the DMS.

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Section: Introductionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Prepubertal ovariectomy alters dorsomedial striatum indirect pathway neuron excitability and explore/exploit balance in female mice

Delevich

Wilbrecht

2021

Preprint

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“…Furthermore, these animals also exhibited more rapid reductions in both darting and freezing behaviors during extinction, and thus darting may be a form of active coping that promotes long-term reductions in fear. Studies have also shown that female rats tend to be more risk aversive than male rats and display greater active avoidance ( Orsini et al, 2016 ; Orsini et al, 2021 ), which may contribute to greater vulnerability to anxiety-related disorders in women compared to men ( Li and Graham, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Adolescent Alcohol Exposure Results in Sex-specific Alterations in Conditioned Fear Learning and Memory in Adulthood

2022

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The present study used auditory fear conditioning to assess the impact of repeated binge-like episodes of alcohol exposure during adolescence on conditioned fear in adulthood. Male and female Long-Evans rats were subjected to adolescent intermittent ethanol (AIE) exposure by vapor inhalation between post-natal day 28 and 44. After aging into adulthood, rats then underwent fear conditioning by exposure to a series of tone-shock pairings. This was followed by cued-tone extinction training, and then testing of fear recovery. In male rats, AIE exposure enhanced conditioned freezing but did not alter the time-course of extinction of cued-tone freezing. During subsequent assessment of fear recovery, AIE exposed rats exhibited less freezing during contextual fear renewal, but greater freezing during extinction recall and spontaneous recovery. Compared to males, female rats exhibited significantly lower levels of freezing during fear conditioning, more rapid extinction of freezing behavior, and significantly lower levels of freezing during the tests of fear recovery. Unlike males that were all classified as high conditioners; female rats could be parsed into either a high or low conditioning group. However, irrespective of their level of conditioned freezing, both the high and low conditioning groups of female rats exhibited rapid extinction of conditioned freezing behavior and comparatively low levels of freezing in tests of fear recovery. Regardless of group classification, AIE had no effect on freezing behavior in female rats during acquisition, extinction, or fear recovery. Lastly, exposure of male rats to the mGlu5 positive allosteric modulator CDPPB prevented AIE-induced alterations in freezing. Taken together, these observations demonstrate sex-specific changes in conditioned fear behaviors that are reversible by pharmacological interventions that target mGlu5 receptor activation.

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“…Rats were placed in the same operant chambers used for the RDT with a single lever (the same lever used as the small, “safe” reward lever in the RDT) extended. In each session, the number of responses required to earn one food pellet began with one, and increased in a geometric sequence until the rats reached their “breakpoint,” or the point at which rats ceased lever pressing (Garman et al, 2021; Hernandez et al, 2017; Orsini et al, 2021). The number of lever presses, number of rewards earned, and the ratio at which rats ceased lever pressing (i.e., breakpoint) were the primary measures of interest.…”

Section: Methodsmentioning

confidence: 99%

“…This “up-and-down” method (Crocker & Russell, 1984) continued in this manner until at least three shock thresholds (or the shock intensities at which motor responses were elicited) were observed. These values were averaged and submitted to data analysis (Orsini et al, 2021).…”

Section: Methodsmentioning

confidence: 99%

Chronic cocaine causes age-dependent increases in risky choice in both males and females.

Blaes¹,

Shimp²,

Betzhold³

et al. 2022

Behavioral Neuroscience

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Individuals who use cocaine exhibit maladaptive decision-making, overweighting rewards, and underweighting potential risks. We previously showed that chronic cocaine self-administration in young adult male rats causes long-lasting increases in risk taking. The present study expanded upon these findings to determine whether effects of cocaine on risk taking depend on the route of cocaine administration and extend to females. To address the former question, rats in Experiment 1 were trained on the Risky Decisionmaking Task (RDT), received passively administered cocaine, and were retested in the RDT. Surprisingly, passive cocaine had no effect on risk taking. Experiment 2 determined whether cocaine self-administration increases risk taking in females in a manner comparable to males. Males and females were trained in the RDT, underwent cocaine self-administration, and were retested in the RDT. Unexpectedly, cocaine selfadministration had no effect on risk taking in either sex. Because Experiments 1 and 2 involved cocaine exposure at a considerably older age than in previous work, Experiments 3 and 4 determined if cocaine effects on risk taking depend on the age of exposure. Rats began cocaine self-administration at postnatal (PN) day 77 (Experiment 3) or passive cocaine injections starting on PN day 63 (Experiment 4) and were tested in the RDT 3 weeks after cocaine cessation. In these experiments, cocaine increased risk taking in both sexes. These results reveal a limited time window during young adulthood of vulnerability to the effects of chronic cocaine on risk taking.

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Regulation of risky decision making by gonadal hormones in males and females

Cited by 32 publications

References 76 publications

Prepubertal ovariectomy alters dorsomedial striatum indirect pathway neuron excitability and explore/exploit balance in female mice

Prepubertal ovariectomy alters dorsomedial striatum indirect pathway neuron excitability and explore/exploit balance in female mice

Adolescent Alcohol Exposure Results in Sex-specific Alterations in Conditioned Fear Learning and Memory in Adulthood

Chronic cocaine causes age-dependent increases in risky choice in both males and females.

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