Anorexia nervosa (AN) has the highest mortality rate of any psychiatric disease, yet available treatments are largely ineffective, in part due to a lack of insight into the neurobiological drivers that underpin the condition. Functional neuroimaging in AN patients suggests that hyperactive cognitive neurocircuitry contributes to pathological body weight loss. Using pathway specific chemogenetics, we hypothesized that decreasing activity in neurons of the medial prefrontal cortex (PFC) with direct projections to ventral reward circuits would improve body weight maintenance in the activity-based anorexia (ABA) rat model and impact on cognitive flexibility in touchscreen operant paradigms.
Female Sprague-Dawley rats (n=33; 6 wks old) underwent bilateral stereotaxic injections of retrogradely-transporting Cre (AAV-pmSyn1-EBFP-Cre) into the nucleus accumbens (NAc) and coincident injections of either inhibiting (AAV-hSyn-DIO-hM4D(Gi)-mCherry), activating (AAV-hSyn-DIO-hM3D(Gq)-mCherry) or control (AAV-hSyn-DIO-mCherry) DREADD viruses into the PFC. During exposure to the ABA paradigm, which involves unhindered access to a running wheel and time-limited (90 min) access to food, all rats were administered clozapine-n-oxide (CNO) daily (0.3-3 mg/kg i.p.) at the onset of the dark phase. For assessment of cognitive performance and flexibility in an operant learning paradigm, a separate cohort of animals (n=24; 3-6 months old) underwent injections of AAV constructs and CNO administration as described above.
Chemogenetic inhibition of PFC-NAc projection neurons prevented body weight loss during ABA (χ2=8.77, p=0.013) by increasing food anticipatory activity (FAA; p=0.011) and subsequent food intake (F=4.14, p=0.025). Conversely, activation of this pathway exacerbated hyperactivity induced by food restriction (F=6.06, p=0.006). There were no significant effects of prefrontal modulation on visual discrimination learning or cognitive flexibility.
Our data indicate that prefrontal circuits impact on food intake and running activity in ABA, but this does not correlate with behavioural measures of cognitive flexibility.