Developmental disruption of the mediodorsal thalamus alters prefrontal dopamine D2 receptor expression and prefrontal–accumbal neuronal recruitment during latent inhibition

Introduction The mediodorsal thalamus (MD) is a higher-order thalamic nucleus that plays a central role in the maturation and function of prefrontal cortical circuits. Although developmental MD dysfunction has been implicated in cognitive deficits associated with neurodevelopmental disorders, the underlying molecular and circuit mechanisms remain poorly understood. Here, we investigated whether neonatal MD lesions produce persistent alterations in latent inhibition (LI), prefrontal dopamine D2 receptor (D2R) expression, and neuronal recruitment within the MD–prefrontal cortex (PFC)–nucleus accumbens (NAc) circuit. Methods Bilateral excitotoxic MD lesions were induced in Sprague–Dawley rats on postnatal day 4 (MD lesion n = 35; MD Sham n = 35). In adulthood, LI was assessed using a conditioned taste aversion paradigm. Neuronal activation was evaluated by c-Fos immunohistochemistry, whereas D2R expression was quantified by immunohistochemistry, Western blotting, and quantitative PCR. The ability of the D2R antagonist haloperidol to restore LI and neuronal activity was also examined. Results and discussion Neonatal MD lesions produced a persistent impairment of LI accompanied by reduced task-related c-Fos expression in the PFC and NAc. These functional abnormalities were associated with a selective increase in prefrontal D2R expression at the transcript, protein, and cellular levels, whereas no changes were observed in the secondary motor cortex. Importantly, haloperidol administration during stimulus pre-exposure restored LI and normalized c-Fos activation in the PFC and NAc of MD-lesion animals without affecting sham controls. These findings demonstrate that early MD dysfunction induces long-lasting remodeling of prefrontal dopaminergic signaling and disrupts recruitment of the MD–PFC–NAc circuit during selective attention. They identify altered D2R signaling as a potential mechanism linking developmental thalamic dysfunction to persistent cognitive deficits.