Impairments in operant probabilistic reversal learning in BTBR T+tf/J male and female mice.

Autism spectrum disorder (ASD) presents with two core symptoms, impairments in social communication and the presence of restricted, repetitive behaviors (RRBs). RRBs are commonly linked to a lack of behavioral flexibility, having a significant negative impact on daily functioning for ASD individuals and their caregivers. Commonly utilized tests of behavioral flexibility employ a traditional deterministic reward approach where choices are either correct or incorrect throughout testing. The incorporation of an 80 %/20 % probabilistic reversal learning paradigm allows for the examination of flexible behavior in the face of variable outcomes, a more ecologically relevant approach. In this task, one specific choice is reinforced on 80 % of trials and the opposite or incorrect choice is reinforced on 20% of trials. Upon successful discrimination learning, the reward contingencies are switched so that the correct choice is now reinforced 20% of trials and the incorrect choice reinforced 80 % of trials, making it the new optimal choice. This translational task has been previously validated in ASD individuals and animal models of ASD, including the BTBR T + tf/J strain. Our lab and others have demonstrated that male BTBR T + tf/J mice have higher expression of lower order RRBs and display deficits in spatial probabilistic reversal learning tasks using a T-maze apparatus. Instead, female BTBR mice do not express the same lower order RRBs and results are mixed on whether females demonstrate similar probabilistic reversal learning deficits in a T-maze. Therefore, the purpose of this study was to assess the validity of using operant chambers to examine BTBR mouse performance on an 80 %/20 % probabilistic reversal learning task and to also examine the sex-specific differences in reversal learning performance in both mouse strains. Results show that BTBR mice, irrespective of sex, were impaired on the reversal learning, requiring more days and trials to reach reversal criterion compared to C57BL/6J mice. These results parallel previous strain findings in the spatial dependent T-maze task in male mice. Further error analysis showed that the impaired behavioral flexibility was due to elevated regressive errors and lose-shift probabilities. BTBR mice have more difficulty maintaining new choice patterns compared to C57BL/6J mice, which supports findings utilizing a spatial T-maze task. Together, these findings further support the use of the BTBR mouse as preclinical models of ASD due to their validity as an ASD model.

A multivariate regressor of patterned dopamine release predicts relapse to cocaine.

Understanding mesolimbic dopamine adaptations underlying vulnerability to drug relapse is essential to inform prognostic tools for effective treatment strategies. However, technical limitations have hindered the direct measurement of sub-second dopamine release in vivo for prolonged periods of time, making it difficult to gauge the weight that these dopamine abnormalities have in determining future relapse incidence. Here, we use the fluorescent sensor GrabDA to record, with millisecond resolution, every single cocaine-evoked dopamine transient in the nucleus accumbens (NAc) of freely moving mice during self-administration. We reveal low-dimensional features of patterned dopamine release that are strong predictors of cue-induced reinstatement of cocaine seeking. Additionally, we report sex-specific differences in cocaine-related dopamine responses related to a greater resistance to extinction in males compared with females. These findings provide important insights into the sufficiency of NAc dopamine signaling dynamics-in interaction with sex-for recapitulating persistent cocaine seeking and future relapse vulnerability.

Acute serotonin 1B/1A receptor activation impairs behavioral flexibility in C57BL/6J mice.

Pharmacological activation of the serotonin (5-HT) 1B and 5-HT1A receptors has been shown to induce OCD-like perseverative circling and locomotor stereotypy in rodents. Although, several studies have examined how activation of these receptors facilitates these motor-associated OCD-like behaviors, it is not known how acute 5-HT1B and 5-HT1A activation impacts behavioral inflexibility, a common trait related to OCD. The current study examined how acute 5-HT1B/1A receptor agonist RU24969 treatment at 0.01, 0.1, and 1.0 mg/kg impacted behavioral flexibility in both female and male C57BL/6J mice. Behavioral flexibility was tested using a spatial reversal learning task, with probabilistic reward contingencies. In addition, locomotor activity and anxiety-like behaviors were also measured. RU24969 at 0.1 and 1.0 mg/kg impaired behavioral flexibility in both female and male C57BL/6J mice. RU24969 treatment at 1.0 mg/kg reduced locomotor activity in male mice, although RU24969 treatment did not significantly reduce locomotor activity in female mice. In the open field, 1.0 mg/kg elevated anxiety-like behavior in male mice only. Overall, these results demonstrate that acute 5-HT1B and 5-HT1A receptor activation leads to impairments in behavioral flexibility, a common trait associated with OCD.

Serotonin 6 receptor modulation reduces locomotor activity in C57BL/6J mice.

The serotonin 6 receptor (5-HT6) is a more recently identified therapeutic target for several neuropsychiatric disorders. While the 5-HT6 receptor has gained interest as a target for novel therapeutics, determining the basic sex differences is lacking in the literature. To address this, the present study examined the effects of 5-HT6 receptor modulation on locomotor activity and open field measures of anxiety in C57BL/6J mice. Female and male mice were tested after acute treatment with either 5-HT6 receptor antagonist SB 271046 or 5-HT6 receptor agonist EMD 386088. Acute 5-HT6 receptor blockade with SB 271046 attenuated locomotor activity in C57BL6/J mice, irrespective of sex. When locomotor activity was analyzed for six 10 min time blocks, 0.1, 5, or 15 mg/kg of SB 271046 reduced locomotor activity for the initial 40 min of testing, but only 5 and 15 mg/kg SB 271046 exhibited a reduction in locomotor activity for at least 60 min. EMD 386088 only attenuated locomotor activity when mice were treated with the high dose of 15 mg/kg EMD 386088. This was true for all time blocks except for the 40-50 min time block. In addition, EMD 386088 at the 15 mg/kg dose reduced locomotor activity in female mice more than males during the 20-30 and 30-40 minute time blocks. Analysis of the anxiolytic properties of 5-HT6 receptor modulation via the open field, showed that SB 271046 did not demonstrate anxiogenic properties in either sex at the doses tested. Instead, 15 mg/kg EMD 386088 produced an anxiogenic effect in both female and male mice. Together these findings highlight the differing impact of specific 5-HT6 receptor modulation on locomotor activity in C57BL/6J mice.

Differences in the expression of restricted repetitive behaviors in female and male BTBR T + tf/J mice.

Autism spectrum disorder (ASD) is characterized by the expression of restricted repetitive behaviors (RRBs) and impairments in social recognition and communication. Epidemiological studies demonstrate males are three times more likely than females to be affected. Although this is the case, more recent studies suggest females may be underrepresented in these numbers due to standard clinical measures of RRBs and social behaviors. In addition, many studies examining mouse models of ASD exclude females due to the sex disparity in diagnoses. The present study examined how female and male BTBR T + Itpr3tf /J (BTBR) compare to control C57BL/6J mice on tests of RRBs (probabilistic reversal learning, repetitive grooming, spontaneous alternation, and marble burying) and social behaviors (three chambered social approach task). Utilizing a spatial reversal learning test with 80/20 probabilistic feedback, in which ASD individuals have exhibited deficits, we find that female BTBR mice do not show the same impairment found in male BTBR mice. Interestingly, control female C57BL/6J mice required more trials to reach criterion. Female BTBR mice expressed comparable rates of repetitive grooming, marble burying and spontaneous alternation compared to female C57BL/6J mice. Male BTBR mice expressed higher rates of grooming behavior and locomotor activity compared to male C57BL/6J mice, as found in previous studies. Similarly, male BTBR mice showed a reduction in both measures of social approach compared to controls. Both male and female BTBR mice showed a reduction in sniff time for the stranger mouse compared to controls. Together these findings demonstrate how female BTBR mice do not display the RRB profile expressed by male BTBR mice. Testing of repetitive behaviors in ASD needs to better reflect the sex differences in how RRBs manifest in females compared to their extensively researched male counterparts.