Isolation rearing effects on probabilistic learning and cognitive flexibility in rats

Abstract

Isolation rearing is a neurodevelopmental manipulation that produces neurochemical, structural, and behavioral alterations in rodents that in many ways are consistent with schizophrenia. Symptoms induced by isolation rearing that mirror clinically relevant aspects of schizophrenia, such as cognitive deficits, open up the possibility of testing putative therapeutics in isolation-reared animals prior to clinical development. We investigated what effect isolation rearing would have on cognitive flexibility, a cognitive function characteristically disrupted in schizophrenia. For this purpose, we assessed cognitive flexibility using between- and within-session probabilistic reversal-learning tasks based on clinical tests. Isolation-reared rats required more sessions, though not more task trials, to acquire criterion performance in the reversal phase of the task, and were slower to adjust their task strategy after reward contingencies were switched. Isolation-reared rats also completed fewer trials and exhibited lower levels of overall activity in the probabilistic reversal-learning task than did the socially reared rats. This finding contrasted with the elevated levels of unconditioned investigatory activity and reduced levels of locomotor habituation that isolation-reared rats displayed in the behavioral pattern monitor. Finally, isolation-reared rats also exhibited sensorimotor gating deficits, reflected by decreased prepulse inhibition of the startle response, consistent with previous studies. We concluded that isolation rearing constitutes a valuable, noninvasive manipulation for modeling schizophrenia-like cognitive deficits and assessing putative therapeutics.

Figure 1. Summary of Study Design

Rats were initially weaned and either isolated or grouped into triads for the rest of the study. Tasks presented in this article are highlighted in grey.

Figure 2. Effects of Isolation Rearing on Prepulse Inhibition of the Startle

Response Isolation-reared rats (isolates) had decreased levels of prepulse inhibition (PPI) compared to socially reared rats (socials). pp3, pp6, pp12: prepulse intensity of 3, 6, or 12 dB over background. Values at 8 weeks (a) and 54 weeks (b) post-weaning are expressed as mean ± SEM. Asterisks (*p < 0.05) denote significant differences compared to socials; asterisks next to the group name reflect an overall main effect of Rearing rather than a significant difference at any individual prepulse intensity.

Figure 3. Effects of Isolation Rearing on Locomotion and Exploratory Behavior in the Behavioral Pattern

Monitor Crossings (a) decreased from the first to the second half of the test in both isolates and socials. However, a significant Rearing x Session Period interaction reflected the fact that crossings decreased less in isolates over time than in socials. This finding was confirmed by the fact that locomotor habituation (b) was significantly lower in isolates compared to socials. There was a trend (p = 0.073) towards more holepokes (c) in isolates, and isolates also performed more rears (d) than socials. Values are expressed as mean ± SEM. Asterisks (*p < 0.05) denote significant differences compared to socials.

Figure 4. Effects of Task Phase on Performance in the Between-Sessions Probabilistic Learning Task

Rats required more sessions (a) and more trials (b) to reach criterion performance in the reversal phase compared to the initial learning phase. Initial: initial learning phase; reversal: reversal-learning phase. Values are expressed as mean ± SEM. Pound signs (###p < 0.0001) denote significant differences between initial learning phase and reversal phase; asterisks (**p < 0.01) denote significant differences compared to socials. Rats that did not reach criterion during the reversal-learning phase are excluded from the analysis due to ANOVA requirements.

Figure 5. Effects of Isolation Rearing on Performance in the Between-Sessions Probabilistic Learning Task

There was a strong trend (p = 0.054) for isolates to require more sessions to reach criterion performance in the initial learning phase (a), and isolates required significantly more sessions to reach criterion in the reversal phase (b). Isolates did not differ significantly from socials in terms of reversals completed during the duration of the experiment (c). Isolates performed fewer trials per session (d) compared to socials. There were no significant differences regarding trials to initial acquisition (e) and trials to first reversal (f) between isolates and socials. Values are expressed as mean ± SEM. Asterisks (*p < 0.05) denote significant differences compared to socials. The depicted analyses include rats that did not reach criterion during the reversal-learning phase.

Figure 6. Effects of Isolation Rearing on Target Win-Stay and Lose-Shift Ratios in the Between-Sessions Probabilistic Learning Task

Rats increased their target win-stay ratio and decreased their target lose-shift ratio during the first three days of the initial learning phase (a, b) and again during the first three days of the reversal phase (c, d). Isolates exhibited less increase in their target win-stay ratio and less decrease in their non-target win-stay ratio compared to socials. Values are expressed as mean ± SEM. Asterisks (*p < 0.05, **p < 0.01) denote significant differences compared to socials.

Figure 7. Effects of isolation rearing on performance in the within-session probabilistic learning task

Isolates completed fewer reversals per session (a) and performed fewer trials per session (b) compared to socials. Over time, all rats completed more reversals per session and performed more trials per session. Values are expressed as mean ± SEM. Asterisks (*p < 0.05, **p < 0.01) denote significant differences compared to socials.

Figure 8. Effects of Isolation Rearing on Target Win-Stay and Lose-Shift Ratios in the Within-Session Probabilistic Learning Task

During the initial learning phase, rats increased their target win-stay ratio over time (a); there were no systematic changes over time in target lose-shift ratio (b). During the reversal-learning phase, there was a trend (p = 0.089) towards lower target win-stay ratios (c) in isolates compared to socials. All rats decreased their target lose-shift ratio (d) over time during the reversal-learning phase. Values are expressed as mean ± SEM.