Early-life cocaine interferes with BDNF-mediated behavioral plasticity

Abstract

An important aspect of goal-directed action selection is differentiating between actions that are more or less likely to be reinforced. With repeated performance or psychostimulant exposure, however, actions can assume stimulus-elicited-or "habitual"-qualities that are resistant to change. We show that selective knockdown of prelimbic prefrontal cortical Brain-derived neurotrophic factor (Bdnf) increases sensitivity to response -outcome associations, blocking habit-like behavioral inflexibility. A history of adolescent cocaine exposure, however, occludes the "beneficial" effects of Bdnf knockdown. This finding highlights a challenge in treating addiction-that drugs of abuse may bias decision-making toward habit systems even in individuals with putative neurobiological resiliencies.Both humans and rodents can learn to associate specific actions with their outcomes. Such actions are considered "goal-directed," meaning their performance is sensitive to changes in the predictive relationship between the behavior and its outcome. Extended training, certain reinforcement schedules, and drugs of abuse can induce a shift from goal-directed to automated, or "habitual," response strategies that are defined by insensitivity to changes in the contingency between the behavior and the outcome (Yin et al. 2008;Balleine and O'Doherty 2010). Within the prefrontal cortex, the prelimbic subregion is intimately linked with goal-directed decision-making. For example, rodents with prelimbic-selective lesions are insensitive to changes in outcome value or modifications in response-outcome associative contingencies (Balleine and Dickinson 1998;Corbit and Balleine 2003;Killcross and Coutureau 2003).Under some conditions, overexpression of the neurotrophin BDNF within the prelimbic cortex also confers habit-like behavioral inflexibility (Graybeal et al. 2011;Gourley et al. 2012). These findings predict that site-selective Brain-derived neurotrophic factor (Bdnf) knockdown might, conversely, augment goal-directed decision-making. Moreover, site-selective knockdown may protect against habits that result from pathological stimuli such as cocaine. This is critical because stimulus-response habits are considered etiological factors in addiction (Jentsch and Taylor 1999;Everitt and Robbins 2005).An important aspect of goal-directed decision-making is differentiating between actions that are more or less likely to be reinforced. Here we trained BALB/c mice to respond for food pellets on two distinct nose poke apertures using a continuous reinforcement schedule. We then modified the schedule such that 50% of the responses on one aperture were reinforced 1 sec after the response. Responding on the other aperture had no consequences; instead, food pellets were delivered noncontingently, "for free," at a rate matched to that of the prior session (Gourley et al. 2013a,b). In this case, only 2.2% of pellets were delivered within 1 sec after a response (Fig. 1). We used these testing parameters (further elaborated below) to ascertain whether targeted...

GABAAα1-Mediated Plasticity in the Orbitofrontal Cortex Regulates Context-Dependent Action Selection

“…By contrast, GABA A a3 is upregulated following heterozygous deletion (Zhou et al, 2013). Mice with oPFC-targeted GABA A a1 knockdown were unable to select actions based on their consequences, developing instead habit-like behavioral inflexibility, recapitulating the effects of early-life cocaine exposure (Hinton et al, 2014) and chronic stressor exposure (Dias-Ferreira et al, 2009), among other manipulations modeling chronic psychiatric illness in rodents (reviewed by Schwabe et al, (2011);Schwabe and Wolf, (2013)). Our findings thus provide a neuroanatomical substrate by which GABA A a1 dysfunction may contribute to addiction, depression, and other stressor-related psychopathologies.…”

“…Notably, when the number of 'non-degraded' responses was divided by the number of 'degraded' responses to generate a preference score (Hinton et al, 2014), control mice and mice with M2-targeted knockdown significantly preferred the non-degraded response, a ratio significantly 41 (one-sample t-test compared to 1, both po0.03; Figure 2c inset). Meanwhile, the oPFC knockdown mice, as a group, responded at chance levels not differing from 1 (t 6 ¼ 1.8, p ¼ 0.13), suggesting that mice with oPFC-targeted knockdown may be biased toward habit-based response strategies.…”

“…In another session, only the opposite aperture is available, and responding is reinforced using a variable ratio 2 schedule of reinforcement for 25 min. Thus, one response becomes significantly more predictive of reinforcer delivery than the other (Hinton et al, 2014). The order of these sessions and the location of the 'degraded' aperture within the chambers are counter balanced.…”

“…Similarly, if rats were trained to perform two discrete responses for two discrete reinforcers and the likelihood of reinforcement associated with one response was decreased, typical rats preferentially performed the remaining response (eg, Colwill and Rescorla, (1986); Balleine and Dickinson, (1998)). Rodents can also differentiate between two actions when both actions result in identical outcomes, as here (Trapold, 1970;Gourley et al, 2012Gourley et al, , 2013aSwanson et al, 2013;Hinton et al, 2014), Figure 2 Dissociable effects of orbitofrontal prefrontal cortex (oPFC)-and M2-targeted GABA A a1 silencing on action selection strategies. (a) Histological representations of viral vector infection are represented on images from the Mouse Brain Library (Rosen et al, 2000).…”

Connections of the Mouse Orbitofrontal Cortex and Regulation of Goal-Directed Action Selection by Brain-Derived Neurotrophic Factor

“…Responding produced no programmed consequences. Thus, one response became significantly more predictive of reinforcement than the other (see(20)). Both apertures were available during a subsequent 10min.…”