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

Abstract

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.

Sex and timing of gonadectomy relative to puberty interact to influence weight, body composition, and feeding behaviors in mice

“…A study by Wang et al found that estradiol treatment to OVX rats increased perseverative responding in an operant task and promoted a less efficient strategy in pursuit of food reward (Wang et al, 2008). Relatedly, we observed that prepubertal OVX females were less perseverative compared to sham females in an odor-based reversal task that was rewarded by food (Delevich et al, 2021). ERα signaling may negatively regulate cost sensitivity – i.e.…”

“…In addition to changes in growth and metabolism, peripuberty may be a sensitive period for the organization of adult behaviors across multiple domains including social, cognitive, and affective (Delevich and Wilbrecht, 2020; Larsen and Luna, 2018; Piekarski et al, 2017b; Schulz and Sisk, 2016). In particular, there is a growing interest in the influence of puberty and gonadal sex steroids on cognitive and decision-making processes (Delevich et al, 2021; Laube et al, 2017; Master et al, 2020; Orsini et al, 2022; Piekarski et al, 2017a). As food is a common primary reinforcer, it is important to understand how gonadal sex steroids influence motivation or willingness to work for food within contexts relevant to operant decision-making tasks.…”

The estrous cycle and 17β‐estradiol modulate the electrophysiological properties of rat nucleus accumbens core medium spiny neurons

“…129 Sex differences and estradiol sensitivity between MSN subtypes remains an active avenue of research. 127,130 These data predict that D2 subtype MSNs exhibit enhanced sensitivity to estradiol action upon mEPSC amplitude. Further testing with D1 or D2 labeled neurons in a relevant animal model must be conducted to confirm this prediction.…”

“…Rheobase is a strong predictor of whether a MSN is a D1 or D2 MSN subtype (D1 > D2; as reviewed previously 127,128 ), however, these strict definitions of MSN subtypes tend to break down in the nucleus accumbens core 129 . Sex differences and estradiol sensitivity between MSN subtypes remains an active avenue of research 127,130 . These data predict that D2 subtype MSNs exhibit enhanced sensitivity to estradiol action upon mEPSC amplitude.…”

A neural substrate of sex-dependent modulation of motivation by value

“…Compatible with this idea, the ACC is thought to be important for regulating exploratory behavior 68,[73][74][75] . Furthermore, sex differences in exploration have been reported in a reinforcement learning task 7 and exploratory choices in a reversal learning task have been linked to the effect of sex hormones on D2R MSNs in the DMS in females 76 .…”