Functional and structural plasticity contributing to obesity: roles for sex, diet, and individual susceptibility

Abstract

The role of cortico-striatal pathways in cue-triggered motivational processes have been extensively studied. However, recent work has begun to examine the potential contribution of plasticity in these circuits to obesity. Despite the inclusion of women in human obesity studies examining neurobehavioral alterations in cue-triggered motivation, preclinical studies have focused mainly on male subjects. This lack of female subjects in preclinical research had led to a gap in the basic understanding of the neural mechanisms underlying over-eating in females. In this review, we highlight recent work from our lab and others that has begun to elucidate how diet, obesity, and individual susceptibility to weight gain influence functional and structural plasticity within the nucleus accumbens and prefrontal cortex in adult rats. As is the case throughout neuroscience, studies of females or sex differences are largely lacking in this area. Thus, below we describe preliminary neurobehavioral results from female studies in our labs and point out areas for future investigation.

Effects of the estrous cycle and ovarian hormones on cue-triggered motivation and intrinsic excitability of medium spiny neurons in the Nucleus Accumbens core of female rats

“…However, how motivational responses to food cues are affected by the estrous cycle or elevations in ovarian hormones is unknown. In addition, while individual susceptibility to obesity is accompanied by enhanced incentive motivational responses to food cues and increased intrinsic excitability of MSNs within the NAc of males, studies in females are lacking (see Introduction and Alonso-Caraballo et al, 2018 ). Here, we show that intrinsic excitability of NAc MSNs and conditioned approach behavior are enhanced in female obesity-prone vs. obesity-resistant rats when measured during metestrus/diestrus.…”

“…Food intake is not only regulated by homeostatic feedback, but external signals including food cues also influence the motivation to eat independent of hunger state ( Derman and Ferrario, 2018a , 2018b ; Holland, 1977 ). These cue-triggered urges to seek out and consume food contribute to opportunistic eating that drives obesity ( Ferrario et al, 2016 ; Ferrario, 2017 ; Stice et al, 2013 ) and are more pronounced in male obesity-susceptible vs. -resistant populations ( Robinson et al, 2015 ; Derman and Ferrario, 2018a ; Alonso-Caraballo et al, 2018 ). Conditioned approach behavior was stronger in female obesity-prone vs. obesity-resistant rats ( Fig.…”

“…These human studies suggest that enhanced neurobehavioral responses to food cues may promote the development of obesity. However, identifying pre-existing differences is not feasible in human studies and there is limited understanding of how ovarian hormones influence brain mechanisms governing cue-triggered food seeking (see Alonso-Caraballo et al, 2018 for additional discussion).…”

Effects of hM4Di activation in CamKII basolateral amygdala neurons and CNO treatment on Sensory-Specific vs. General-PIT; refining PIT circuits and considerations for using CNO

“…Pavlovian conditioned stimuli often acquire the ability to control instrumental behaviors, a phenomenon known as Pavlovian-to-Instrumental transfer that can be observed in rodents (Walker, 1942;Cartoni et al, 2016) as well as humans (Colagiuri Lovibond, 2015;De Tommaso et al, 2018;Hogarth et al, 2018). This phenomenon is thought to play an important role in a wide range of behaviors that are essential for survival, and in the development of problematic appetitive behaviors that drive addictions and obesity (Wyvell Berridge, 2000;Berridge Robinson, 2003;Bouton, 2011;Boutelle Bouton, 2015;Alonso-Caraballo et al, 2018;Derman Ferrario, 2018;Watson et al, 2018). Consistent with the preclinical literature, studies in humans also find support for alterations in PIT and its underlying neural and psychological processes in obesity and internet gaming disorders (Lehner et al, 2017;Vogel et al, 2018).…”

Insulin enhances presynaptic glutamate release via opioid receptor-mediated disinhibition

“…Glutamatergic transmission within the nucleus accumbens (NAc) mediates many aspects of motivation and decision-making in response to food, sex, and drugs of abuse, as well as to environmental stimuli paired with these rewards. For example, food-and drug-seeking behaviors rely on activation of the NAc (Di Ciano et al, 2001;Kalivas, 2009;Wolf, 2016), and repeated exposure to drugs of abuse or palatable foods enhances NAc excitatory transmission that underlies food-and drug-seeking behaviors (Oginsky et al, 2016;Wolf, 2016;Dong et al, 2017;Alonso-Caraballo et al, 2018;Derman and Ferrario, 2018;Alonso-Caraballo et al, In Press). Thus, identifying neural mechanisms that regulate NAc excitatory transmission is fundamental to understanding the neurobiology of normal and aberrant motivation.…”