Early social experience is critical for the development of cognitive control and dopamine modulation of prefrontal cortex function

Abstract

Social experiences during youth are thought to be critical for proper social and cognitive development. Conversely, social insults during development can cause long-lasting behavioral impairments and increase the vulnerability for psychopathology later in life. To investigate the importance of social experience during the juvenile and early adolescent stage for the development of cognitive control capacities, rats were socially isolated from postnatal day 21 to 42 followed by re-socialization until they reached adulthood. Subsequently, two behavioral dimensions of impulsivity (impulsive action in the five-choice serial reaction time task (5-CSRTT) and impulsive choice in the delayed reward task) and decision making (in the rat gambling task) were assessed. In a separate group of animals, long-lasting cellular and synaptic changes in adult medial prefrontal cortex (PFC) pyramidal neurons were determined following social isolation. Juvenile and early adolescent social isolation resulted in impairments in impulsive action and decision making under novel or challenging circumstances. Moreover, socially isolated rats had a reduced response to enhancement of dopaminergic neurotransmission (using amphetamine or GBR12909) in the 5-CSRTT under challenging conditions. Impulsive choice was not affected by social isolation. These behavioral deficits were accompanied by a loss of sensitivity to dopamine of pyramidal neurons in the medial PFC. Our data show long-lasting deleterious effects of early social isolation on cognitive control and its neural substrates. Alterations in prefrontal cognitive control mechanisms may contribute to the enhanced risk for psychiatric disorders induced by aberrations in the early social environment.

Figure 1

Effect of social isolation during postnatal day 21–42 followed by re-socialization on adult performance in the 5-choice serial reaction time task. (a) Amount of premature responses, ie, impulsive action, (b) percentage of correct responses, ie, accuracy and (c) errors of omission, under baseline conditions (BAS: visual stimulus presented 5 s after trial initiation, 1 s stimulus duration) or long intertrial interval (L ITI: visual stimulus presented 7 s after trial initiation), short stimulus duration (S STIM: 0.5 s stimulus duration), high event rate (HER: intertrial interval 2.5 s). Group size was n=12. SOC=socially housed rats during PND 21–42, ISO=socially isolated rats during PND 21–42. Asterisk indicates p<0.05 compared with SOC. Line on top of bar indicates p<0.05 compared with baseline. All data are expressed as mean±SEM.

Figure 2

Effect of social isolation during postnatal day 21–42 followed by re-socialization on adult performance in the 5-choice serial reaction time task. (a,d) Amount of premature responses, ie, impulsive action; (b,e) percentage of correct responses, ie, accuracy; (c,f) errors of omission, under (a–c) baseline conditions (visual stimulus presented 5 s after trial initiation) or (d–f) long ITI conditions (visual stimulus presented 7 s after trial initiation). Pharmacological challenges consisted of treatment with 0.5 mg/kg of amphetamine (AMPH), 10 mg/kg of the selective dopamine reuptake inhibitor GBR12909 (GBR), 1 mg/kg of the selective serotonin reuptake inhibitor citalopram (CIT), and 3 mg/kg of the selective noradrenaline reuptake inhibitor atomoxetine (ATO). In total, n=10–12 animals per treatment group were included in the analysis. SOC=socially housed rats during PND 21–42, ISO=socially isolated rats during PND 21–42, SAL=saline treatment. Asterisk indicates p<0.05 compared with SOC group. Line on top of bar indicates p<0.05 compared with baseline or saline treatment. All data are expressed as mean±SEM.

Figure 3

Effect of social isolation during postnatal day 21–42 followed by re-socialization on impulsive choice in the DRT during adulthood. Percentage of choice for the large reward expressed per block of trials with increasing delays under (a) baseline, (b) increased delays, and (c) 1 mg/kg amphetamine challenge. In total, n=10–12 animals per treatment group were included in the analysis. AMPH=amphetamine, SOC=socially housed rats during PND 21–42, ISO=socially isolated rats during PND 21–42. Asterisk indicates p<0.05 compared with saline treatment. All data are expressed as mean±SEM.

Figure 4

Effect of social isolation during postnatal day 21–42 followed by re-socialization on decision making in the rat gambling task during adulthood. Percentage of choice for the advantageous vs disadvantageous options during (a,b) the first free sample choice session, and (c) pharmacological challenges after stable baseline performance. Pharmacological challenges consisted of 1 mg/kg of amphetamine, 10 mg/kg GBR12909, 3 mg/kg citalopram, and 3 mg/kg atomoxetine. In total, n=10–12 animals per treatment group were included in the analysis. SOC=socially housed rats during PND 21–42, ISO=socially isolated rats during PND 21–42. Asterisk indicates p<0.05 and double asterisks indicate p<0.01 difference between options. All data are expressed as mean±SEM.

Figure 5

Effect of social isolation during postnatal day 21–42 followed by re-socialization on synaptic response size in mPFC. EPSP amplitude before and after bath-application of a combination of SK38393 (5 μM) and quinpirole (1 μM) in adult SOC animals (a; n=14 cells from nine animals, double asterisks indicate P<0.01 compared with aCSF; b: example trace). EPSP amplitude in animals socially isolated between P21 and 42 (ISO; c; n=17 cells from eight animals; d: example trace). A summary of the EPSP amplitude following application of SKF38393 and quinpirole is shown in e. Location of pyramidal cells, mostly in infralimbic mPFC layer V, recorded from is shown in f (white circles are cells from SOC animals, gray circles are cells from adult animals socially isolated from PND 21–42; ISO). Asterisk indicates P<0.05 compared with SOC group. Data are expressed as mean±SEM.