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. Author manuscript; available in PMC: 2022 Dec 21.
Published in final edited form as: Psychopharmacology (Berl). 2022 Oct 4;239(11):3697–3709. doi: 10.1007/s00213-022-06243-0

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

Margaret K Tanner 1, Jazmyne K P Davis 1, Jennifer Jaime 1,2, Nicolette A Moya 1,3, Alyssa A Hohorst 1, Kelsey Bonar 1, Kelsey A Abrams 1,4, Nashra Jamil 1, Rebecca Han 1, Troy J Hubert 1,5, Nadja Brown 1, Esteban C Loetz 1, Benjamin N Greenwood 1
PMCID: PMC9768838  NIHMSID: NIHMS1855326  PMID: 36195731

Abstract

Rationale

Exercise participation remains low despite clear benefits. Rats engage in voluntary wheel running (VWR) that follows distinct phases of acquisition, during which VWR escalates, and maintenance, during which VWR remains stable. Understanding mechanisms driving acquisition and maintenance of VWR could lead to novel strategies to promote exercise. The two phases of VWR resemble those that occur during operant conditioning and, therefore, might involve similar neural substrates. The dorsomedial (DMS) dorsal striatum (DS) supports the acquisition of operant conditioning, whereas the dorsolateral striatum (DLS) supports its maintenance.

Objectives

Here we sought to characterize the roles of DS subregions in VWR. Females escalate VWR and operant conditioning faster than males. Thus, we also assessed for sex differences.

Methods

To determine the causal role of DS subregions in VWR, we pharmacologically inactivated the DMS or DLS of adult, male and female, Long-Evans rats during the two phases of VWR. The involvement of DA receptor 1 (D1)–expressing neurons in the DS was investigated by quantifying cfos mRNA within this neuronal population.

Results

We observed that, in males, the DMS and DLS are critical for VWR exclusively during acquisition and maintenance, respectively. In females, the DMS is also critical only during acquisition, but the DLS contributes to VWR during both VWR phases. DLS D1 neurons could be an important driver of VWR escalation during acquisition.

Conclusions

The acquisition and maintenance of VWR involve unique neural substrates in the DS that vary by sex. Results reveal targets for sex-specific strategies to promote exercise.

Keywords: Wheel running, Exercise, Habit, Dorsolateral striatum, Dorsomedial striatum, Dorsal striatum, Dopamine, Sex differences

Introduction

Regular physical activity improves broad aspects of mental and physical health and reduces the risk of chronic disease (Booth et al. 2017; Ruegsegger and Booth 2018), but only a small percentage of adults achieve recommended levels of exercise (Troiano et al. 2008). The lack of engagement in regular exercise is a critical problem as incidence rates of disease related to sedentary behavior are rising (Booth et al. 2017).

Voluntary wheel running (VWR) is a rodent model of physical activity that is widely used to study the biological effects of exercise (Greenwood and Fleshner 2019; Hastings et al. 2022; Novak et al. 2012; Sherwin 1998). However, the translational validity of VWR is limited by a lack of understanding of the biological processes driving the behavior. The pattern of rodent VWR follows two distinct phases (Basso and Morrell 2017; Greenwood and Fleshner 2019; Lattanzio and Eikelboom 2003; Novak et al. 2012). During the acquisition phase, rats escalate running distance over days. During the maintenance phase, rats exhibit stable, high levels of nocturnal running across days. Interestingly, this pattern of VWR closely resembles that of operant reinforcement, such as lever pressing for various rewards, which is often separated into distinct phases described as escalation and maintenance (Ahmed and Koob 1998; Stewart 2000). VWR also functions as a natural reinforcer (Basso and Morrell 2015; Belke and Wagner 2005; Greenwood et al. 2011; Herrera et al. 2016; Lett et al. 2000; Trost and Hauber 2014) and activates the mesolimbic dopamine (DA) pathway (Greenwood et al. 2011; Herrera et al. 2016; Werme et al. 2002) thought to encode reward value (Sackett et al. 2017). Together, these data suggest that VWR could be governed by similar principles as operant conditioning.

The circuitry underlying the acquisition and maintenance of operant behavior has been well studied and involves different regions of the dorsal striatum (DS) (Graybiel and Grafton 2015; Hilario et al. 2012; Knowlton et al. 1996; Malvaez and Wassum 2018; Yin and Knowlton 2006; Yin et al. 2004). The associative dorsomedial striatum (DMS) contributes to the acquisition of operant behavior by employing goal-directed strategies, during which actions become associated with their outcomes (Yin et al. 2005). Following extensive training, operant behavior can become habitual, during which actions become insensitive to changes in outcome value and are mediated by the sensorimotor dorsolateral striatum (DLS) (Yin and Knowlton 2006; Yin et al. 2004). If VWR is mediated by principles underlying operant reinforcement, then it stands to reason that it would rely on similar neural circuitry.

The majority of DS neurons are medium-spiny neurons expressing either low-affinity DA D1 or high-affinity DA D2 receptors (Graveland and DiFiglia 1985; Kreitzer 2009). Since DA, D1-, and D2-expressing neurons in the DS have been implicated in movement (Carlsson et al. 1957, 1958; Graybiel et al. 1994; Kravitz and Kreitzer 2012) and goal-directed and habitual operant behaviors (Faure et al. 2005; van Elzelingen et al. 2022; Wickens et al. 2007), these neurons could contribute to the acquisition and/or maintenance of VWR. Prior studies have implicated the prefrontal cortex and nucleus accumbens (NAc) in regulating VWR (Basso and Morrell 2015; Zhu et al. 2016), and investigated adaptations within the DMS and DLS following exercise and the role of D1 and D2 receptors (Basso and Morrell 2015; Bauer et al. 2020; Foley and Fleshner 2008; Greenwood 2019; Greenwood et al. 2011; Knab and Lightfoot 2010; Rhodes et al. 2005; Roberts et al. 2012; Ruegsegger and Booth 2017; Ruiz-Tejada et al. 2022; Zhu et al. 2016), but to our knowledge, no studies have yet tested the causal role of DS subregions in the acquisition and maintenance of VWR, nor whether D1 and D2 neurons are differentially recruited during the acquisition and/or maintenance phases of VWR.

Sex differences during both phases of VWR have been observed. Female rats escalate VWR faster and run greater distances than do males (Basso and Morrell 2017; Eikelboom and Mills 1988). The majority of this sex difference is driven by females running the most during the proestrus (Pro) phase of the estrous cycle (Anantharaman-Barr and Decombaz 1989; Basso and Morrell 2017; Eckel et al. 2000; Eikelboom and Mills 1988). Since females are particularly susceptible to several diseases associated with sedentary behavior (Breslau 2009; Steel et al. 2014), it is important to understand if mechanisms underlying exercise differ between the sexes. However, whether there are sex differences in the mechanisms underlying the acquisition and maintenance of voluntary exercise is unknown.

The goal of the current study is to investigate the role of DS subregions in governing VWR behavior and to determine if sex differences exist. We use pharmacological inactivation to temporarily disrupt neural activity in the DMS or DLS during the acquisition and maintenance phases of VWR to determine the casual role of these regions during the different phases of VWR. The involvement of D1 neurons in the DMS and DLS is explored using double fluorescent in situ hybridization (FISH) for D1 (Drd1) and cfos mRNAs. Since most DS neurons are either D1 or D2, and Drd1 and Drd2 mRNAs are almost completely segregated in the DS (Bouchet et al. 2018; Gerfen et al. 1990), single cfos is used as a marker of the activity of putative D2-expressing neurons. We observe that DS subregions contribute differentially to VWR depending on VWR history and sex, and that the activity of DLS D1-expressing neurons could be an important driver of VWR escalation. Interestingly, the DLS contributes to VWR during early VWR acquisition in females, but not in males; an observation that could explain sex differences in the escalation of VWR. Results provide new insight for the development of sex-specific strategies aimed at promoting exercise.

Materials and methods

Animals and housing

Age-matched, female (n = 94) and male (n = 80) Long-Evans (Charles River) rats, weighing 189.1 ± 1.4 g to 245.7 ± 6.6 g (females and males, respectively) at the time of arrival were single-housed in Nalgene plexiglas cages (45.5 L × 24 W × 21 H cm) containing a locked running wheel (1.081 m circumference; Starr Life Sciences, Oakmont, PA). Rats were maintained on a 12 h light–dark cycle (lights on 0600–1800) in a temperature (22 °C)- and humidity (30%)-controlled vivarium accredited by the Association for Assessment and Accreditation of Laboratory Animal Care located at the University of Colorado Denver Auraria campus. Food (Teklad 2020X rodent diet, Envigo, Madison, WI) and water were available ad libitum. Rats were allowed to acclimate to vivarium conditions for 1 week prior to experimentation, during which time all wheels were rendered immobile. Following the acclimation period, rats were randomly assigned to either VWR or locked wheel (locked) conditions. Wheels in the cages of VWR rats were unlocked for the duration of the experiments, while wheels in the cages of the locked rats remained locked. No other cage enrichment other than a locked or mobile wheel was provided. Running distances were recorded daily using VitalView Analysis software (Starr Life Sciences) and distance was calculated by multiplying revolutions by circumference. Rats used in the locomotor activity experiment were single-housed in cages without running wheels with crinkle paper provided for enrichment. The estrous cycle phase was determined by vaginal lavage conducted every 24 h for the duration of the experiments according to our published protocols (Bouchet et al. 2017). All experiments were approved by the University of Colorado Denver Institutional Animal Care and Use Committee.

Stereotaxic surgery

Bilateral 26-guage guide cannula (Plastics One, Roanoke, VA, USA) were targeted to 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 atlas of Paxinos and Watson (1998). Animals received subcutaneous injections of carprofen (5 mg/kg) and penicillin G (22,000 IU/rat) at induction and every 24 h for 72 h post-surgery. All surgeries were carried out under ketamine (75.0 mg/kg i.p.) and medetomidine (0.5 mg/kg i.p.) anesthesia. Atipamezole (0.5 mg/kg i.p.) was given as the reversing agent to speed recovery. Rats recovered for 1 week before experimental procedures began. After surgery, rats were handled daily during which time dummy cannulae were removed and replaced to maintain the patency of the lumen. Cannulae placements were verified in all rats by inspection of brain tissue (Olympus BX53). Rats with misplaced cannulae were excluded from the experiment.

Procedures

To determine the causal role of the DMS and DLS in the acquisition and maintenance of VWR, rats received microinjections of either saline or a cocktail of fluorescent muscimol (0.03 nmol/uL; Thermo Fisher Scientific, Waltham, MA) and baclofen (0.3 nmol/uL; Musc/Bac) into either the DMS (n = 20 males; n = 27 females) or DLS (n = 20 males; n = 27 females). Volume was 1 μL/hemisphere and flow rate was 0.5 μL/min. Each rat received both saline and Musc/Bac during both the acquisition and maintenance phases. During the acquisition phase, on the 4th and 5th nights of VWR, rats received saline or Musc/Bac and were then allowed to VWR for 2 h. Saline and Musc/Bac microinjections were made in a counterbalanced manner. During the maintenance phase, on the 28th and 29th night of VWR, rats again received saline or Musc/Bal in a counterbalanced manner and VWR distances were again recorded for 2 h (see Fig. 2A for experimental timeline). As female rats have been reported to run more during the proestrus phase of the estrous cycle (Pro) compared to other phases (Basso and Morrell 2017), the experiment was powered to detect potential estrous phase differences in DMS or DLS dependency. Drug doses were based on a prior study injecting Musc/Bac into DS subregions (Corbit et al. 2012). Microinjectors, which extended 0.5 mm below the guide tip, were left in place for 2 min following infusion to allow for diffusion. Three days later, rats were randomly assigned to receive a 5th microinjection of either saline or Musc/Bac, allowed to run for 90 min, and then perfused. Extracted brains were sliced at 35 μm on a cryostat and processed for cFos immunohistochemistry (IHC; Bouchet et al. 2018; Herrera et al. 2016; Supplementary Information).

Fig. 2.

Fig. 2

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Role of the dorsomedial (DMS) and dorsolateral (DLS) striatum in voluntary wheel running (VWR). A Experimental timeline. Rats received saline and muscimol/baclofen (Musc/Bac) injections into either the DMS or DLS during both the acquisition phase (days 4 and 5 after start of VWR) and maintenance phase (days 28 and 29 after start of VWR). Since VWR behavior peaks during the first few h after the start of the active cycle (Fig. 1E and F), saline or Musc/Bac was injected 15 min prior to the start of the active cycle and VWR was monitored for 2 h prior to wheels being locked. B Fluorescent muscimol depicts spread of injection within the DLS (scale bar = 500 μm). C Graphical reconstruction of smallest (dark red) and largest (bright red) muscimol spread within the DMS (top row) and DLS (bottom row) included in the experiment. Coronal sections modified from Paxinos and Watson (Paxinos 1998). D Running distance over a 2 h period following saline or muscimol/baclofen (Musc/Bac) injection into the DMS or DLS during the acquisition phase of VWR. E Running distance over a 2 h period following saline or muscimol/baclofen injection into the DMS or DLS during the maintenance phase of VWR. F Running distance of rats injected with Musc/Bas into the DMS or DLS during the acquisition phase expressed as a percent difference from the same rats injected with saline. G Running distance of rats injected with Musc/Bas into the DMS or DLS during the maintenance phase expressed as a percent difference from the same rats injected with saline. H Regression analysis showing the relationship between average daily distance run during the first 3 days of the experiment and the effect of intra-DLS Musc/Bac expressed as a % of saline. I Regression analysis showing the relationship between average daily distance run during the first 3 days of the experiment and the effect of intra-DMS Musc/Bac expressed as a % of saline. J Male (n = 7 after 1 exclusion due to misplaced cannulae) and female (n = 8) rats received intra-DLS saline or muscimol/baclofen (Musc/Bac) on alternating days for 4 days (2 saline and 2 Musc/Bac injections each) prior to placement into Med Associates locomotor activity chambers for 1 h. The data collected over the 2 d of injections were averaged to yield one value each for saline and Musc/Bac. K Rats were injected a 3rd time with Musc/Bas into the DMS or DLS on day 32 and running distance was recorded for 90 min prior to perfusion for cFos immunohistochemistry (IR). L cFos IR expressed as a % of the saline group for rats injected in the DMS. (M) cFos IR expressed as a % of the saline group for rats injected in the DMS. Representative photomicrographs depicting cFos in the DLS of female rats injected with (N) saline or (O) Musc/Bac into the DLS. Arrows point to some of the many cFos-positive cells. Scale bar = 85 μm. Bars represent group means ± SEM. *p < 0.05

To begin to investigate the role of D1-expressing neurons in the acquisition and maintenance of VWR, we used FISH to quantify VWR-induced cfos mRNA within Drd1 mRNA-expressing neurons in the DMS and DLS during both the acquisition and maintenance phases of VWR (see Fig. 3A for experimental timeline). Non-cannulated male (n = 32) and female (n = 32) rats were randomly assigned to either locked or VWR conditions. On the 4th (acquisition; n = 10 per sex) or 28th (maintenance; n = 10 per sex) night of VWR, rats were removed from their home cages between 15 and 40 min after the start of the active cycle and killed by rapid decapitation. Locked rats (n = 12 per sex) were killed at both time points. Brains were removed, immediately frozen, stored at − 80, and subsequently sliced frozen on a cryostat at 10 μm. FISH procedures and quantification occurred according to our published protocols (Bouchet et al. 2018; Greenwood et al. 2011; Herrera et al. 2016; Supplementary Information). Trunk blood was collected in EDTA tubes, spun at 3000G for 15 min at 4 °C, and plasma was stored at − 80. Corticosterone was measured with an enzyme-linked immunosorbent assay (Mika et al. 2015; Supplemental Information). Adrenals and thymus were removed, defatted, and weighed.

Fig. 3.

Fig. 3

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Activity of dopamine receptor 1 (Drd1) mRNA-expressing striatal neurons during voluntary wheel running (VWR). A Experimental timeline. B Photomicrograph depicting double fluorescent in situ hybridization for Drd1 mRNA (red), cfos mRNA (green), double-labeled cells (yellow), and DAPI (blue) in the DLS. Scale bar = 50 um. The inset shows regions counted. Percentage of Drd1 mRNA-expressing neurons co-expressing cfos mRNA are shown in the C dorsomedial striatum (DMS), D dorsolateral striatum (DLS), E nucleus accumbens shell (NAcS), and F nucleus accumbens core (NAcC). G Number of single cfos mRNA-positive cells in the DLS, H plasma corticosterone following 30 min of VWR. Bars represent group means ± SEM. *p < 0.05

Locomotor activity

A cohort of male and female rats (n = 8/group) not exposed to running wheels were used to assess the effects of DLS inactivation on general locomotor activity. Cannulated rats received a microinjection of either saline or Musc/Bac bilaterally into the DLS 15 min prior to being placed for 1 h into locomotor chambers (17″ X 17″ X 12″; Med Associates, Fairfax, VT) which use beam breaks to calculate the total distance traveled. Each rat received 2 injections of both saline and Musc/Bac on alternating days (over 4 days) in a counterbalanced manner and served as their own controls.

Statistical analysis

Running data were analyzed with repeated measures ANOVA comparing male vs. female or male vs. female estrous phases separately. Body weight was analyzed using repeated measures ANOVA with sex and exercise as factors. Running distances following saline or Musc/Bac injections were analyzed using repeated measures ANOVA with sex, brain region, and drug as factors. Locomotor activity data were averaged to yield one value each for saline and Musc/Bac, which were compared with repeated measures ANOVA with sex as the factor. Levels of cFos immunoreactivity (IR) were analyzed using ANOVA with brain region examined, brain region injected, sex, and drug as factors. The percent of Drd1-positive cells co-expressing cfos mRNA, total number of Drd1-positive cells, single cfos mRNA levels, and Cort were analyzed using ANOVA with sex and exercise group (locked, VWR acquisition and VWR maintenance) as factors. Relationships between running distance and various dependent measures were explored using regression analyses. The Shapiro–Wilk and Brown-Forsythe tests verified normality and equal variance of the data, respectively, prior to running ANOVAs. Bonferroni’s post hoc analyses were performed when required. Group differences were considered significant when p < 0.05.

Results

Sex differences in VWR behavior

Average nightly running distance escalated over weeks (main effect of time: F(3, 246) = 166; p < 0.0001), females ran more than males (main effect of sex: F(1, 82) = 39.4; p < 0.0001), and females escalated more rapidly than males (time by sex interaction: F(3, 246) = 5.5; p = 0.001; Fig. 1A). Females ran the most while in the Pro phase of the estrous cycle (time by sex/estrous phase interaction: F(9, 453) = 5.1; p < 0.0001 Fig. 1B). Confirming that escalation of daily VWR occurred during VWR acquisition (week 1) but not maintenance (week 4), both sexes displayed escalation of daily VWR during week 1 (F(6, 492) = 79.5; p < 0.0001; Fig. 1C) and reached steady daily VWR by week 4 (F(6, 492) = 0.4; p = 0.8, Fig. 1D). Females ran more than males starting from the first day of wheel access (Fig. 1C) and escalated more rapidly than males during acquisition (interaction between time and sex: F(6, 492) = 6.5; p < 0.0001; Fig. 1C).

Fig. 1.

Fig. 1

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Sex differences in voluntary wheel running (VWR) behavior. A Average daily distance run of rats assigned to VWR conditions for at least 28 d. Each data point in the violin plot represents a single subject’s data point, coded by sex. **Females different from males (p < 0.0001). B Average daily distance run of male and female rats during specific phases of the estrous cycle: proestrus (Pro), estrus (Est), and metestrus or diestrus (Met/Di). *Pro different from all other groups (p < 0.01); **Pro different from all other groups (p < 0.0001); θ Met/Di different from males (p < 0.05); Φ all estrous phases different from males (p < 0.01). C. Distance run during the 7 days (acquisition). *Females different from males (p < 0.01); **Females different from males (p < 0.0001). D Distance run during the last 7 days (maintenance). *Females different from males (p < 0.01). E Diurnal pattern of VWR during acquisition (week 1). *Pro different from all other groups (p < 0.05); θ Pro different from males (p < 0.05); Φ all estrous phases different from males (p < 0.05). F Diurnal pattern of VWR during maintenance (week 4). *Pro different from all other groups (p < 0.05); θ Pro different from males (p < 0.05); Φ all estrous phases different from males (p < 0.05). G Average distance run in the inactive cycle. *p < 0.05; **p < 0.01; ***p < 0.001. Bars and symbols points represent group means ± SEM

The circadian pattern of VWR was also examined. Since females run the most while in Pro and running distance during other estrous phases are comparable (Fig. 1B), the circadian pattern of VWR during Met, Di, and Est were collapsed (Not Pro) and compared to the circadian pattern of males and females during Pro. Interestingly, females began VWR during the latter part of the inactive cycle, hours prior to males. This sex difference in circadian timing of VWR was largest when females were in Pro, and grew more robust as VWR progressed from acquisition (sex/phase × time interaction: F(46, 3588) = 3.2; p < 0.0001; Fig. 1E) to maintenance (sex/phase × time interaction: F(46, 3588) = 5.0; p < 0.0001; Fig. 1F). Average distance run during the entire inactive cycle during weeks 1 and 4 were compared between groups with repeated measures ANOVA. Females ran more than males during the entire inactive cycle, and this difference was most robust during Pro (main effect of sex/phase: F(2,156) = 16.2; p < 0.0001; Fig. 1G). Distance run during the inactive cycle escalated over time in females, but not males (sex/phase × time interaction: F(2,156) = 4.0; p = 0.02; Fig. 1G). Females weighed less than males and VWR attenuated weight gain in both sexes (Fig. S1, Supplementary Information).

Different DS subregions govern voluntary exercise depending on exercise history and sex

To study the causal role of DS subregions in VWR, rats received either saline or Musc/Bac into the DMS or DLS during both the acquisition and maintenance phases. An experimental design is shown in Fig. 2A. An example of the physical spread of fluorescent Musc within the DLS is shown in Fig. 2B. After the exclusion of rats with cannulae tips outside of the DMS and DLS boundaries defined in Greenwood and Fleshner (2019), the physical spread of fluorescent Musc was observed to be within the limits shown in Fig. 2C. Final group sizes were as follows: male DMS n = 11, male DLS n = 13, female DMS n = 20, female DLS n = 21. Musc/Bac injections had similar effects in females regardless of estrous cycle phase during acquisition (interaction between acquisition phase, brain region, and drug; F(1, 70) = 3.2; p = 0.08) or maintenance (interaction between maintenance phase, brain region, and drug; F(1, 70) = 0.06; p = 0.8), so the females injected at various estrous phases were pooled into one female group.

As expected, females ran greater distances during the 2 h period after injection compared to males, regardless of drug injection (main effect of sex; F(1, 61) = 62.5; p < 0.0001). Additionally, the effect of DMS or DLS inactivation depended on the running phase (interaction between DS subregion and time; F(3, 183) = 4.2; p = 0.006). Post hoc analyses indicated that, in males, DMS inactivation reduced VWR during the acquisition phase (Fig. 2D), but not maintenance phase (Fig. 2E); whereas DLS inactivation had no effect on VWR during the acquisition phase (Fig. 2D), but reduced VWR during the maintenance phase (Fig. 2E). Interestingly, inactivation of either DMS or DLS reduced VWR during the acquisition phase in females (Fig. 2D), but, like males, only DLS inactivation reduced VWR during the maintenance phase in females (Fig. 2E). Comparing the % difference in VWR between saline and Musc/Bac injections revealed significant interactions between sex and DS subregion (F(1,61) = 4.1; p < 0.05) and DS subregion and time (F(1,61) = 12.4; p < 0.001). Although DMS inactivation essentially eliminated VWR during the acquisition phase in males, DMS and DLS inactivation only reduced VWR by ~ 50% during the acquisition phase in females (Fig. 2F). DLS inactivation impacted VWR during the maintenance phase similarly between sexes (Fig. 2G).

The more rats of either sex ran during the first 3 d of the experiment, the more DLS inhibition reduced VWR (F(1, 28) = 4.6; p = 0.03; R2 = 0.15; Fig. 2H). Although we might expect that DMS inhibition during acquisition would have the biggest effect in rats that ran the least, this relationship was not significant (F(1, 29) = 0.21; p = 0.65; R2 = 0.007; Fig. 2I). No significant relationships between running distance and effects of DMS or DLS inhibition were found during maintenance. Intra-DLS Musc/Bac had no effect on general locomotor activity in either sex (main effect of drug: F(1, 13) = 0.6; p = 0.45; sex by drug interaction: F(1, 13) = 0.4; p = 0.5; Fig. 2J).

The effect of Musc/Bac on VWR during the maintenance phase was replicated on day 32, when Musc/Bac again reduced VWR in both sexes when injected into the DLS, but not DMS (main effects of sex: F(1, 54) = 14.12; p = 0.0004; main effect of drug: F(1, 54) = 6.4; p = 0.01; interaction between drug and brain region: F(1, 54) = 3.6; p = 0.06; Fig. 2K). To compare the magnitude of Musc/Bac-induced inhibition between DS subregions, cFos IR was expressed as a % of the saline group for each DS subregion. Musc/Bac significantly reduced cFos IR only in the region in which it was injected (interaction between brain region examined, brain region injected, and drug: F(1, 50) = 6.2; p = 0.01; Fig. 2L and M). Representative photomicrographs depicting cFos in the DLS of female rats injected with saline or Musc/Bac into the DLS are shown in Fig. 2N and O, respectively.

A bout of voluntary exercise differentially recruits striatal Drd1-expressing neurons depending on exercise history and sex

Double FISH was used to determine the effects of VWR on cfos mRNA expression within Drd1-expressing neurons in striatal subregions of male and female rats during the acquisition and maintenance of VWR. An experimental design is shown in Fig. 3A. An example photomicrograph depicting the mRNAs examined is shown in Fig. 3B. Figure 3B inset shows the regions examined. Since the estrous cycle does not influence which DS subregion governs female VWR (Fig. 2D and E), the experiment was not powered to detect estrous cycle effects. No differences were observed between Locked rats killed after 4 days or 28 days (for example, the % of Drd1-positive cells co-expressing cfos mRNA in the DMS (F(1, 20) = 0.14; p = 0.7) or DLS (F1, 20) = 0.93; p = 0.3)), so these rats were pooled into one locked group for each sex. VWR increased the percentage of Drd1-positive cells expressing cfos mRNA in the DMS of both sexes, during both the acquisition and maintenance phases (main effect of exercise: F(2, 56) = 5.1; p = 0.009; Fig. 3C). VWR increased the activity of Drd1-expressing neurons in the DLS of males during the maintenance, but not acquisition, phase, but the activity of Drd1-expressing DLS neurons was increased in the DLS by VWR at both time points in females (interaction between sex and exercise: F(2, 56) = 3.1; p < 0.05; Fig. 3D). A similar pattern was observed in the NAcS, although only the main effect of exercise was significant (F(2, 56) = 4.6; p = 0.01; Fig. 3E). No significant group differences were observed in the NAcC (Fig. 3F).

Single cfos mRNA- and total Drd1 mRNA-positive cell counts are shown in Table 1. As the vast majority of DLS neurons are D1- or D2-expressing medium-spiny neurons, and Drd1 and Drd2 mRNAs are almost completely segregated in the DS (Bouchet et al. 2018; Gerfen et al. 1990), single cfos represents the activity of putative D2-expressing neurons. No group differences in single cfos-positive cells were observed in any region except in the DLS (Fig. 3G). Although the pattern of single cfos mRNA data in the DLS resembled that of Fig. 3D, only the main effect of exercise was significant (F(2, 56) = 4.5; p = 0.01). Females had fewer total Drd1-positive cell counts in the NAcS relative to males (Table 1), but no other group differences in Drd1 levels were noted.

Table 1.

Single Drd1 mRNA and cfos mRNA levels in the striatum; θmain effect of sex (F(1, 56) = 8.3; p < 0.01); *main effect of exercise (F(2, 56) = 4.5; p = 0.01)

Brain
Region		 Male
Sed
(± SEM)		 Male
4-d VWR
(± SEM)		 Male
30-d VWR
(± SEM)		 Female
Sed
(± SEM)		 Female
4-d VWR
(± SEM)		 Female
30-d VWR
(± SEM)
# single DMS 49.19 (6.20) 54.11 (4.17) 60.68 (7.06) 54.03 (3.58) 53.14 (5.18) 45.96 (4.95)
Drd1 DLS 48.70 (6.56) 54.27 (5.49) 63.02 (7.86) 57.65 (4.24) 55.31 (5.33) 52.82 (5.00)
mRNA-positive cells NAcC 57.6 (5.80) 51.68 (5.38) 57.62 (5.01) 47.78 (5.09) 45.03 (6.91) 49.66 (6.79)
NAcSθ 48.37 (6.92) 56.85 (7.69) 66.41 (12.9) 36.13 (6.73) 35.94 (8.15) 39.86 (8.43)
# single DMS 17.45 (4.49) 23.20 (4.40) 26.06 (6.64) 16.08 (4.48) 25.18 (5.38) 26.12 (8.38)
cfos DLS* 14.02 (3.05) 12.09 (3.37) 22.56 (5.04) 9.98 (1.88) 20.93 (4.23) 25.7 (6.61)
mRNA-positive cells NAcC 15.69 (3.65) 13.9 (4.56) 19.22 (4.18) 16.53 (5.12) 12.60 (2.23) 20.62 (3.51)
NAcS 16.01 (2.95) 19.86 (7.24) 23.30 (5.08) 20.37 (5.74) 16.10 (3.28) 22.58 (4.11)
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To further probe the relationships between neural activity in DS subregions during the two phases of VWR, the ratio of DLS:DMS D1 and putative D2 activity were calculated and related to running distance using regression analysis. In female rats killed during VWR acquisition (Fig. 4A), the average running distance during the first 3 days of VWR was significantly positively correlated with the ratio of DLS:DMS D1 neural activity (F(1, 8) = 8.5; p = 0.02; R2 = 0.52) but not DLS:DMS putative D2 activity (F(1, 8) = 0.87; p = 0.38; R2 = 0.11). Interestingly, this relationship flipped in females during maintenance (Fig. 4B), such that average running distance during the last 3 days of VWR was significantly positively correlated to DLS:DMS putative D2 activity (F(1, 9) = 5.0; p = 0.04; R2 = 0.4), but not DLS:DMS D1 activity (F(1, 9) = 0.7; p = 0.43; R2 = 0.07). Neither relationship was significant in males during acquisition (Fig. 4C; D1: F(1, 8) = 0.53; p = 0.49; R2 = 0.07; D2: F(1, 8) = 0.7; p = 0.44; R2 = 0.08) nor maintenance (Fig. 4D; D1: F(1, 8) = 0.8; p = 0.39; R2 = 0.1; D2: F(1, 8) = 0.17; p = 0.7; R2 = 0.02). No other significant correlations were found.

Fig. 4.

Fig. 4

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Relationships between running distance and neural activity in dorsal striatum subregions. A In females, distance run during the first 3 days (acquisition) predicts the ratio of dorsolateral (DLS):dorsomedial (DMS)D1 neural activity, but not DLS:DMS putative D2 activity (measured using single cfos). B Also in females, distance run during the last 3 days (maintenance) predicts the ratio of DLS:DMS putative D2 activity, but not DLS:DMS D1 neural activity. Neither of these relationships were significant in males, either during C acquisition or D maintenance

Plasma corticosterone levels were higher in females than in males (main effect of sex: F(1, 58) = 43.1; p < 0.0001). VWR increased plasma corticosterone (main effect of exercise: F(2,58) = 4.4; p = 0.01), and this effect was most pronounced in females during the maintenance phase (Fig. 3H). Despite corticosterone being highest in VWR females during the maintenance phase, there were no other indications that VWR elicits chronic stress differentially between the sexes (Fig. S2, Supplementary Information).

Discussion

Here we report the novel findings that the contribution of specific DS subregions to VWR depends on VWR history and sex. In males, the DMS governs the acquisition of VWR, whereas the DLS governs its maintenance. In females, both the DMS and DLS contribute partially to VWR during the acquisition phase, but once in the maintenance phase, VWR maintains a dependency on the DLS but loses its dependency on the DMS. These data reveal critical roles of the DMS and DLS in the acquisition and maintenance, respectively, of VWR in both sexes, whereas the role of the DLS in VWR acquisition is sex-divergent. Although the activity of D1-expressing neurons in the DMS is not restricted to the VWR phase in which the DMS is required for VWR, the activity of D1-expressing neurons in the DLS occurs selectively during the VWR phase during which the DLS is required for VWR. Correlational analyses reveal DLS D1 activity could drive the escalation of VWR and the transition from DMS to DLS-governance of VWR during acquisition, whereas DLS D2 activity may play a more prominent role during maintenance. These results provide fresh insight into the neural control of voluntary physical activity.

Similar to prior reports (Anantharaman-Barr and Decombaz 1989; Basso and Morrell 2017; Eckel et al. 2000; Eikelboom and Mills 1988), we observed that females escalate VWR faster and run greater distances than do males. Sex differences in VWR are present during all estrous phases, but are greatest during Pro. The observation that females begin VWR hours prior to males, during the latter part of the inactive cycle, is consistent with Wollnik and Turek (1988). Although this prior report indicates females begin VWR prior to males, the observed effect was reported to be greatest during Est, rather than Pro (Wollnik and Turek 1988). These authors, however, determined the estrous phase in only a small subset of rats, whereas the estrous phase was measured daily in all the rats used here. Regardless of the estrous phase, the data taken together indicate that females engage in more VWR during the inactive cycle than do males.

The observed duration-dependent effects of DS subregion inhibition on VWR resemble prior work indicating that operant reinforcement initially depends on a DMS system and later depends on a DLS system as goal-directed behavior becomes habitual (Balleine et al. 2007; Graybiel and Grafton 2015; Hilario et al. 2012; Knowlton et al. 1996; Malvaez and Wassum 2018; Yin and Knowlton 2006; Yin et al. 2004). These data suggest that VWR could be governed by similar principles and mechanisms as operant reinforcement. Furthermore, insofar as goal-directed behavior depends on DMS and habit behavior depends on DLS, the current results suggest that rodent VWR could initially begin as a purposeful, goal-directed behavior that later becomes stamped into habitual behavior repertoires. If so, this strengthens the validity of VWR as a translational model of physical activity, as human exercise is also thought to begin as goal-directed behavior which can become habitual (Beshears et al. 2021; Kaushal and Rhodes 2015; Pfeffer and Strobach 2018; Strobach et al. 2020). Prior data are consistent with this hypothesis. Exposure to stress can suppress goal-directed behavior, while habit behavior is maintained in the face of stress (Schwabe and Wolf 2011). In male rats naïve to VWR, exposure to an acute, severe stressor drastically reduces VWR for at least 4 w (Maier et al. 1990). In contrast, the same stressor only briefly reduces VWR in male rats that have already been running for 4 weeks (Moraska and Fleshner 2001). This could be because rats initially use stress-sensitive goal-directed strategies involving the DMS to govern VWR, whereas stress-resistant habit strategies involving the DLS take over by 4 weeks. Determining whether VWR becomes insensitive to outcome devaluation during maintenance (the gold standard for defining habitual behavior) is required to test this hypothesis.

We found sex differences in the involvement of DS subregions in the acquisition of VWR. DMS inactivation during acquisition completely eliminates male VWR, but only reduces female VWR by ~ 50%. This difference could be due to the DLS being recruited earlier during VWR acquisition in females compared to males, thus allowing the DLS to compensate for DMS inhibition. Indeed, neural activity in the DLS appears during the early acquisition of VWR in females, but not males. The observation that inhibition of either DS subregion during VWR acquisition only partially suppresses VWR in females suggests that females could have greater flexibility in the neural control of early VWR than males. This flexibility is lost with extended training, as DMS inhibition fails to impact VWR during the maintenance phase in either sex. Moreover, it seems that the DMS is unable to compensate for DLS inhibition during the maintenance phase, despite enduring neural activity in the DMS during maintenance.

An intriguing question is whether females, like males, require time to develop DLS dependency over VWR, or whether females recruit the DLS to support VWR from the first day of VWR. Since DLS inhibition produces a larger suppression of VWR in rats that run the most during early acquisition, and females run more than males starting on the first day of VWR, the latter possibility seems plausible. In either case, recruitment of the DLS during early acquisition could explain the particularly rapid escalation of VWR and habit development (Quinn et al. 2007; Schoenberg et al. 2019) noted in females, compared to males. Importantly, DLS inhibition does not seem to be globally suppressing VWR in females by producing a performance deficit, since DLS inhibition has no effect on locomotor activity, per se.

Mechanisms driving the sex difference in the acquisition of VWR remain unknown, but both corticosterone and DA stand out as potential factors. Glucocorticoids facilitate DLS-dependent, stimulus–response learning in humans (Guenzel et al. 2014) and rodents (Goodman et al. 2015). The higher corticosterone levels we observe in females than in males could; therefore, be at least partially responsible for encouraging DLS recruitment during the early acquisition of VWR. Additionally, DA contributes to DLS-dependent habit learning (Faure et al. 2005; Wickens et al. 2007), and evoked DA release in the striatum is greater in females than in males (Becker 1999; Zachry et al. 2021). Although phasic DA release has not yet been measured during VWR, the recruitment of DLS D1-expressing neurons during VWR acquisition in females could be a result of potentiated phasic DA release in the DLS in females compared to males. Sex differences notwithstanding, DA could be most important in determining which DS subregion drives VWR during acquisition, relative to maintenance. During acquisition, the activity of D1-expressing neurons, which are particularly sensitive to phasic DA release (Goto and Grace 2005; Grace et al. 2007), occurs specifically in DS subregions required for VWR during this phase (DMS in males and DMS and DLS in females). This specificity is lost during maintenance, when VWR recruits D1 neurons in the DMS despite DMS activity being unnecessary for VWR. These data are consistent with a prior report indicating enduring DMS activity during both early and late operant training (Vandaele et al. 2019). Studies which measure and manipulate DA dynamics will be required to clarify the role of DA in determining which DS subregion drives VWR.

Correlational analyses reveal potentially diverging roles of D1- and D2-expressing neurons during the different phases of VWR. Although the ratio of DLS:DMS D1 activity is positively correlated to running distance during acquisition in females, this correlation is lost during maintenance. Instead, running distance now predicts DLS:DMS putative D2 activity (measured by singe cfos). These data suggest that DLS D1-expressing neurons could be particularly important during acquisition, perhaps by contributing to escalation and/or the transition from DMS- to DLS-control of VWR. DLS D2-expressing neurons may play a more prominent role in maintaining high levels of VWR during maintenance. Consistent with this interpretation, the performance of a motor skill can become less dependent on D1 receptors over the course of training (Yin et al. 2009), and both D1 and D2 receptors have been implicated in VWR (Beeler et al. 2016; Ebada et al. 2016; Klinker et al. 2013; Zhu et al. 2016). These correlations are not significant in males, possibly because males lack sufficient variability in the running distance required to achieve significant correlations.

In summary, the data presented here demonstrate for the first time that the acquisition and maintenance of VWR involve unique neural substrates in the DS, and the contribution of the DLS to VWR is sex-divergent. These results suggest that VWR, like an appetitive operant condition, could begin as a purposeful, goal-directed behavior that becomes habitual over time. These findings could inform the development of sex-specific strategies to motivate the initial acquisition and long-term maintenance of voluntary exercise behavior in humans.

Supplementary Material

Supplementary Material

Acknowledgements

The authors would like to thank Dr. Erik B. Oleson for proofreading the manuscript.

Funding

Funding for these studies was provided by NIH R15MH114026 awarded to BNG.

Footnotes

Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s00213-022-06243-0.

Declarations

Conflict of interest The authors declare no competing interests.

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