The Role of Mesolimbic Reward Neurocircuitry in Prevention and Rescue of the Activity-Based Anorexia (ABA) Phenotype in Rats

Abstract

Patients suffering from anorexia nervosa (AN) become anhedonic; unable or unwilling to derive normal pleasures and avoid rewarding outcomes, most profoundly in food intake. The activity-based anorexia (ABA) model recapitulates many of the characteristics of the human condition, including anhedonia, and allows investigation of the underlying neurobiology of AN. The potential for increased neuronal activity in reward/hedonic circuits to prevent and rescue weight loss is investigated in this model. The mesolimbic pathway extending from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) was activated using a dual viral strategy, involving retrograde transport of Cre (CAV-2-Cre) to the VTA and coincident injection of DREADD receptors (AAV-hSyn-DIO-hM3D(Gq)-mCherry). Systemic clozapine-n-oxide (CNO; 0.3 mg/kg) successfully recruited a large proportion of the VTA-NAc dopaminergic projections, with activity evidenced by colocalization with elevated levels of Fos protein. The effects of reward circuit activation on energy balance and predicted survival was investigated in female Sprague-Dawley rats, where free access to running wheels was paired with time-limited (90 min) access to food, a paradigm (ABA) which will cause anorexia and death if unchecked. Excitation of the reward pathway substantially increased food intake and food anticipatory activity (FAA) to prevent ABA-associated weight loss, while overall locomotor activity was unchanged. Similar activation of reward circuitry, delayed until establishment of the ABA phenotype, rescued rats from their precipitous weight loss. Although these data are consistent with shifts primarily in food intake, the contribution of mechanisms including energy expenditure to survival remains to be determined. These results will inform the neurobiological underpinnings of AN, and provide insight into the mechanisms of reward circuitry relevant to feeding and weight loss.

The use of chemogenetics in behavioural neuroscience: receptor variants, targeting approaches and caveats

“…More recently, Foldi et al . () also used the CAV approach in VTA → NAc projection neurons and showed that excitation of this projection increased food intake, ameliorating activity‐based anorexia‐induced weight loss. This CAV–DREADD technique has also been used in other neural pathways.…”

A focus on reward in anorexia nervosa through the lens of the activity‐based anorexia rodent model

“…Briefly, this approach involves stereotaxically injecting canine adenovirus (CAV), expressing Cre recombinase (CAV‐2‐Cre) into the NAc, which is retrogradely transported to the VTA and recombines with the separately injected activating DREADD virus tagged with a fluorescent reporter [AAV‐hSyn‐DIO‐hM 3 D(G q )‐mCherry], resulting in activation of this neuroanatomically defined pathway. This strategy revealed that the drastic body weight “free‐fall” associated with ABA can be prevented and rescued by reward circuit activation, leading to an increase in food intake and FAA, with a profound increase in survival (Figure ) . The continuation and extension of these targeted studies will directly inform questions about the necessity and sufficiency of the circuitry underpinning ABA and, potentially, the neurobiology of AN.…”

“…Results for (A) and (B) are expressed as mean± SEM ( & P <.01, # P <.001). Reproduced with permission …”

“…Activation of the reward circuitry promoted survival during prevention of the ABA phenotype (A) in which 80% vs 14% survived [χ 2 =9.95, d.f.=1, P =.002] as well as during rescue experiments (B) in which 75% vs 25% survived [χ 2 =3.97, d.f.=1, P =.046)]. Produced from data in Foldi et al…”

Combining designer receptors exclusively activated by designer drugs and neuroimaging in experimental models: A powerful approach towards neurotheranostic applications

“…Additionally, projection‐specific DREADDs expression can be obtained using Cre‐recombinase expressing canine adenovirus. This Cre‐recombinase expressing canine adenovirus is preferentially retrogradely transported to the neuronal somas, where it can interact with the Cre‐dependent DREADDs constructs to express the DREADDs (Boender et al, ; Foldi, Milton, & Oldfield, ; Roelofs et al, ).…”