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 the interplay between underactive reward and overactive cognitive neurocircuits may underscore pathological body weight loss. Utilising the activity-based anorexia (ABA) rodent model, we have previously shown that chemogenetic activation of the ventral reward circuitry prevents and rescues precipitous body weight loss by increasing food intake. Here, we hypothesised that reducing activity in neurons of the prefrontal cortex with direct projections to ventral reward circuits would similarly improve body weight maintenance in ABA.
Female Sprague-Dawley rats (N=36) underwent bilateral stereotaxic injections of a retrogradely-transporting Cre (AAV-pmSyn1-EBFP-Cre) into the nucleus accumbens (NAc) and coincident injections of either inhibiting [AAV-hSyn-DIO-hM4D(Gi)-mCherry] or activating [AAV-hSyn-DIO-hM3D(Gq)-mCherry] DREADD viruses into the prefrontal cortex (PFC). This dual viral strategy allows for precise modulation of only those PFC neurons that project to the NAc. Rats injected with the blank viral construct (AAV-hSyn-DIO-mCherry) were used as controls. During exposure to the ABA paradigm, which involves unhindered access to a running wheel and time-limited (90 min/day) access to food, all rats were administered CNO daily (0.3-3 mg/kg i.p.) at the onset of the dark phase for a maximum of 10 days.
Contrary to our hypothesis, chemogenetic inhibition of PFC-NAc projection neurons increased susceptibility to body weight loss in ABA (χ1=6.33, p=0.012), by exacerbating running wheel activity compared to controls (F=10.16, p=0.009), with no effect on food intake (t=0.47, p=0.65). Taken together, our data indicate that both ventral reward and executive control circuits respectively impact on food intake and running activity, both essential elements of the ABA phenotype and the AN condition that contribute to pathological body weight loss.