Dietary regulation of silent synapses in the dorsolateral striatum.

Obesity and drugs of abuse share overlapping neural circuits and behaviors. Silent synapses are transient synapses that are important for remodeling brain circuits. They are prevalent during early development but largely disappear by adulthood. Drugs of abuse increase silent synapses during adulthood and may facilitate reorganizing brain circuits around drug-related experience, facilitating addiction and contributing to relapse during treatment and abstinence. Whether obesity causes alterations in the expression of silent synapses in a manner similar to drugs of abuse has not been examined. Using a dietary-induced obesity paradigm, mice that chronically consumed high fat diet (HFD) exhibited increased silent synapses in both direct and indirect pathway medium spiny neurons in the dorsolateral striatum. Both the time of onset of increased silent synapses and their normalization upon discontinuation of HFD occurs on an extended time scale compared to drugs of abuse. These data demonstrate that chronic consumption of HFD, like drugs of abuse, can alter mechanisms of circuit plasticity likely facilitating neural reorganization analogous to drugs of abuse.

Chronic food restriction enhances dopamine-mediated intracranial self-stimulation.

Dopamine-mediated reinforcement and behavioral adaptation is essential to survival. Here, we test the effects of food restriction on dopamine-mediated learning and reinforcement using optical intracranial self-stimulation (oICSS), an optogenetic version of conventional electrical ICSS (also known as brain stimulation reward, BSR). Using mouse genetic lines to express channelrhodopsin selectively in midbrain dopamine neurons, we demonstrate that genetically expressed channelrhodopsin can mediate optically evoked dopamine release and support self-stimulation in a lever-pressing paradigm. Using this midbrain dopamine oICSS preparation, we compare acquisition and rate of pressing in ad libitum versus food restricted mice. Food restriction facilitated both more rapid acquisition of self-stimulation behavior and higher rates of responding; reversing food status after acquisition modulated response vigor in already established behavior. These data suggest that food restriction enhances both the acquisition and expression of dopamine-reinforced self-stimulation responding. These data demonstrate the utility of oICSS for examining changes in reinforcement learning concomitant to neuroadaptations induced in dopamine signaling by experimental manipulations such as food restriction.

Striatal Dopamine D2 Receptors Regulate Cost Sensitivity and Behavioral Thrift.

The role of the dopamine D2 receptor (D2R) in regulating appetitive behavior continues to be controversial. Earlier literature suggests that reduced D2R signaling diminishes motivated behavior while more recent theories suggest that reduced D2R, as has been putatively observed in obesity, facilitates compulsive appetitive behavior and promotes overeating. Using a homecage foraging paradigm with mice, we revisit classic neuroleptic pharmacological studies from the 1970s that led to the 'extinction mimicry' hypothesis: that dopamine blockade reduces reinforcement leading to an extinction-like reduction in a learned, motivated behavior. We complement this with a selective genetic deletion of D2R in indirect pathway medium spiny neurons (iMSNs). Administration of haloperidol shifts foraging strategy toward less effortful, more thrifty pursuit of food without altering consumption or bodyweight. D2R deletion in iMSNs also reduces effort and energy expended toward food pursuit, but without a compensatory shift in foraging strategy, resulting in loss of body weight, an effect more pronounced under conditions of escalating costs as the knockouts fail to adequately increase effort. The selective knockouts exhibit no change in sucrose preference or sucrose reinforcement. These data suggest that striatal D2R regulates effort in response to costs, mediating cost sensitivity and behavioral thrift. In the context of obesity, these data suggest that reduced D2R is more likely to diminish effort and behavioral energy expenditure rather than increase appetitive motivation and consumption, possibly contributing to reduced physical activity commonly observed in obesity.