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.

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.

Impact of specific serotonin receptor modulation on restricted repetitive behaviors.

Restricted, repetitive behaviors (RRBs) are commonly divided into two behavioral categories, lower-order and higher-order RRBs. Individuals displaying lower-order motoric RRBs may express repetitive hand flapping behaviors, body rocking back and forth movements, and continuous body spinning. Higher-order RRBs most commonly cover the behavior inflexibility and cognitive rigidity commonly found in disorders such as autism spectrum disorder and obsessive-compulsive disorder. Various neuropsychiatric disorders are plagued by RRBs yet no FDA-approved treatments have been identified. In rodents, lower-order RRBs are commonly measured through various tasks, such as repetitive self-grooming, marble burying, and stereotypic motor behaviors. This review focuses on the effects that modulation of specific serotonin receptors have on lower-order RRBs. Although there is research examining how changes in 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptor modulation, more research has focused on the 5-HT1A, 5-HT2A, and 5-HT2C receptors. The accumulating data suggest that increasing 5-HT1A activation decreases RRBs while blocking 5-HT1A activation has no effect on RRBs. While there are mixed findings regarding the impact of 5-HT2A modulation on RRBs, the general trend shows mixed effects of 5-HT2A receptor activation RRB expression, whereas blockade generally decreases RRBs. 5-HT2C receptor activation can modulate RRBs in either direction depending on the 5-HT2C drug used, blocking 5-HT2C activation only seems to show therapeutic properties when 5-HT2C activation is already elevated. The other 5-HT receptors have been explored far less but show promise as potential targets for regulating RRBs. Although it is less clear due to the involvement of 5-HT1D, 5-HT1A activation increases RRBs, and blocking 5-HT1A tends to decrease RRBs. 5-HT2B activation could reduce RRBs, while inhibiting 5-HT2B does not impact RRBs. Increasing 5-HT3 has not been shown to affect RRBs. Yet, increases in RRBs have been observed in Htr3a KO mice. 5-HT6 receptor activation can increase RRBs, while blocking 5-HT6 activity tends to decrease RRBs. Lastly, neither increasing or blocking 5-HT7 activity can reduce RRBs. In sum, there is no uniform pattern in whether all specific 5-HT receptors affect RRBs in either direction, instead, there is evidence suggesting that different 5-HT receptors can modulate RRBs in different directions. Further researching the less explored receptors and aiming to understand why these receptors can differently modulate RRBs, may play a key role in developing therapeutics that treat RRBs.

Impact of specific serotonin receptor modulation on behavioral flexibility.

Serotonin (5-HT) is known to play a critical role in regulation of essential neural processes, whereas more recent research highlights serotonin's modulatory effects on cognition and executive functioning. Current examinations have identified specific serotonin receptors for their direct impact on behavioral flexibility. Providing definitive evidence for the impact of specific receptor targets on behavioral flexibility is difficult, due to the range of behavioral tests used. Due to limited studies and the sheer amount of different serotonin receptor targets, beginning to bring these studies together is important for the field. Our current review of the literature aims to differentiate how modulation of specific 5-HT receptors affects behavioral flexibility. Although more studies have examined 5-HT2A, 5-HT2C, and 5-HT6 receptors, it is unclear why this is the case. Above all, there are some paradoxical results pertaining to these receptor targets. There is a clear distinction between 5-HT2A and 5-HT2C, which conveys that these two receptor subtypes have inverse effects when compared to each other. In addition, some findings support one another, such as upregulation of 5-HT6 receptors impairs flexibility, while blockade alleviates this impairment in both drug-induced and disease model rodent studies. Further understanding how modulatory effects of specific 5-HT receptors impact behavioral flexibility is imperative to advance the development of new therapeutics for neuropsychiatric disorders afflicted by behavioral inflexibility.