Patients suffering anorexia nervosa (AN) become anhedonic; unable or unwilling to derive normal pleasures and tend to avoid rewarding outcomes, most profoundly in food intake. Conversely, obesity is a condition that may be potentiated by excessive reward seeking and enhanced motivation for the rewarding properties of food. The activity-based anorexia (ABA) model allows investigation of the underlying neurobiology of AN, especially because it displays many characteristics in common with the human condition, including anhedonia. We aim to exploit this model to highlight the importance of CNS reward in the maintenance of body weight. We hypothesise that increasing the neuronal activity of circuits with predicted involvement in the anhedonia/reward pathways of ABA will prevent associated weight loss.
Female rats (n=24; 6 weeks old) underwent separate bilateral stereotaxic injections of canine adenovirus-2-Cre (CAV-2-Cre) and activating DREADDs [AAV-hSyn-DIO-hM3D(Gq)-mCherry] into the NAcc (shell) and the VTA, respectively. DREADDs reorient in the presence of retrogradely-transported Cre and systemic clozapine-n-oxide (CNO) administration causes mCherry-labelled cells to depolarise with temporal and anatomical specificity. The ABA protocol involves free access to running wheels and time-limited (90 min) access to food, with daily i.p. injections of CNO or saline (control) at the onset of the feeding period.
CNO activates DREADD-expressing, VTA neurons as evidenced by colocalisation with elevated levels of Fos protein, a marker of neuronal activation. Importantly, excitation of this pathway with CNO attenuates the rapid weight loss associated with ABA with a profound effect on survival [χ2(1)=8.14, p=0.004]. Activation also increases food anticipatory activity (FAA) and decreases basal running activity at discrete time periods. The contribution of energy expenditure to body weight maintenance during activation is unclear. These results will inform not only the neurobiological underpinnings of AN but also provide an insight into the mechanisms of reward pathways relevant to feeding and weight loss.