Corticostriatal modulation of sign-traking: double disassociation of medial pre-frontal cortex norepinephrine and Nucleus Accumbens dopamine transmission in mice
Dysfunctional processing of motivationally salient stimuli has been proposed in various behavioral disturbances. For this reason, the NIH and the EC-funded Roadmap for Mental Health Research (ROAMER) identify neural systems and neurobiological mechanisms involved in motivational salience processing among the top research topics in mental health.
The set of experiments proposed by this project will test the hypothesis that attribution of extreme motivational salience to specific cues requires the engagement of a corticostriatal circuit involving dopamine (DA) transmission in the Nucleus Accumbens (NAc) and high tonic norepinephrine (NE) in the medial pre frontal-cortex (mpFC).
To this aim we will perform a double disassociation experiment in male mice of the standard inbred C57BL/6 strain trained in a Pavlovian conditioned approach paradigm. Lever-directed (sign-tracking:ST) responses, a measure of high incentive motivation, will be measured during 12 daily conditioning sessions. On day 13 mice will be implanted with guide cannulas at the mpFC and NAc. Mice in the experimental group will have a cannula unilaterally implanted in mpFC and the other implanted contro-laterally in the NAc. All the other groups will be used as unilateral or bilateral controls. Following 4 days of recovery, a baseline session will be performed followed, 24 h later, by a training session preceded by infusion of an antagonist for adrenergic receptors in the mpFC and/or a DAergic antagonist in the NAc.
Blockade of sign-tracking in the groups of mice receiving the adrenergic antagonist bilaterally in mpFC or the DAergic antagonist bilaterally in the NAc will demonstrate the involvement of frontal cortical NE and mesoaccumbens DA in the expression of sign-tracking. Blockade of sign-tracking in the experimental group will demonstrate that the two responses are interdependent offering support to the tested hypothesis. Lack of effects of unilateral antagonisms will rule out false positive.