Low prefrontal PSA-NCAM confers risk for alcoholism-related behavior

Abstract

The factors underlying vulnerability to alcoholism are largely unknown. We identified in rodents an innate endophenotype predicting individual risk for alcohol-related behaviors that was associated with decreased expression of the neuroplasticity-related polysialylated neural cell adhesion molecule (PSA-NCAM). Depletion of PSA-NCAM in the ventromedial prefrontal cortex was sufficient to render mice unable to extinguish alcohol seeking, indicating a causal role of naturally occurring variation. These data suggest a mechanism of aberrant prefrontal neuroplasticity that underlies enhanced propensity for inflexible addiction-related behavior.

Figure 1

a. Mice were separated by median split into High and Low PIT groups that are significantly different from one another (F_1,62= 41.82; p<.001) on normalized responding (normalized lever presses during Cue On to Cue Off periods), but no effect of Pavlovian approach (F_1,62= .462, p=.5). b. High PIT mice show resistance to extinction on the first session A repeated measures ANOVA revealed an interaction between PIT and session on responding (F_{1, 29}=4.7572, p=.03). Post hoc analyses indicate that there is an effect of Extinction in Low PIT animals (p=.013) but no effect in High PIT animals (p>.7). Responding on subsequent extinction days was equivalent between groups by a repeated measures ANOVA (no effect of PIT x day; p>.2). c. High PIT mice show greater cue-induced reinstatement than Low PIT mice. Repeated measures ANOVA revealed an interaction between PIT and session on active responding (F_1,29= 6.3778, p=.017), as well as a main effect of reinstatement (F_1,29= 8.3147, p<.01). Post-hoc analyses indicate that High PIT mice make a greater number of nosepokes during the reinstatement session than during the last extinction session (p=.016), while Low PIT mice respond equivalently (p=.5), and further, that High PIT mice make a greater number of nosepokes during the reinstatement session than Low PIT mice (p=.0372), indicating that High PIT mice show a greater effect of reinstatement than Low PIT mice. *p<.05, **p<.01, ***p<.001. Error bars ± SEM.

Figure 2

a. High PIT status predicted lower levels of PSA-NCAM in the vmPFC. A repeated measures ANOVA showed a main effect of PIT status on normalized PSA-NCAM expression in the vmPFC (PSA-NCAM/total NCAM; F_1,34=6.0155, p=.015). No interaction was seen, indicating that this effect was consistent across isoforms. Representative bands are cropped from complete blots (Supp. Fig 10). b. Site of endo-N infusion and representative bands showing decreased PSA-NCAM expression at the time of reinstatement. c. Loss of PSA-NCAM in the vmPFC resulted in resistance to extinction across multiple sessions. A main effect of infralimbic endo-N treatment on responding during extinction by repeated measures ANOVA (F_1,13= 5.65, p=.03), but no main effect of PIT status, consistent with a lack of effect on multiple days of extinction in outbred mice, or of day of extinction. d. Treatment with endo-N did not influence cue-induced reinstatement of alcohol seeking during the between sessions reinstatement session (p>.2). Nor was there an interaction between endo-N and session (p>.25) or an effect during a ‘within-session’ test performed to confirm that baseline differences in responding during extinction were not responsible for the lack of effect of prefrontal endo-N treatment on cue-induced reinstatement or that impaired consolidation of extinction learning was responsible for any effects on reinstatement (F_1,16=.89, p>.35). A main effect of session was seen (F_1,16=9.63, p<.01), indicating that all mice significantly increased responding during the reinstatement session. *p<.05, **p<.01, ***p<.001. Error bars ± SEM.