The role of pituitary adenylate cyclase-activating polypeptide neurons in the hypothalamic ventromedial nucleus and the cognate PAC1 receptor in the regulation of hedonic feeding.

Obesity is a health malady that affects mental, physical, and social health. Pathology includes chronic imbalance between energy intake and expenditure, likely facilitated by dysregulation of the mesolimbic dopamine (DA) pathway. We explored the role of pituitary adenylate cyclase-activating polypeptide (PACAP) neurons in the hypothalamic ventromedial nucleus (VMN) and the PACAP-selective (PAC1) receptor in regulating hedonic feeding. We hypothesized that VMN PACAP neurons would inhibit reward-encoding mesolimbic (A10) dopamine neurons via PAC1 receptor activation and thereby suppress impulsive consumption brought on by intermittent exposure to highly palatable food. Visualized whole-cell patch clamp recordings coupled with in vivo behavioral experiments were utilized in wildtype, PACAP-cre, TH-cre, and TH-cre/PAC1 receptor-floxed mice. We found that bath application of PACAP directly inhibited preidentified A10 dopamine neurons in the ventral tegmental area (VTA) from TH-cre mice. This inhibitory action was abrogated by the selective knockdown of the PAC1 receptor in A10 dopamine neurons. PACAP delivered directly into the VTA decreases binge feeding accompanied by reduced meal size and duration in TH-cre mice. These effects are negated by PAC1 receptor knockdown in A10 dopamine neurons. Additionally, apoptotic ablation of VMN PACAP neurons increased binge consumption in both lean and obese, male and female PACAP-cre mice relative to wildtype controls. These findings demonstrate that VMN PACAP neurons blunt impulsive, binge feeding behavior by activating PAC1 receptors to inhibit A10 dopamine neurons. As such, they impart impactful insight into potential treatment strategies for conditions such as obesity and food addiction.

The PACAP Paradox: Dynamic and Surprisingly Pleiotropic Actions in the Central Regulation of Energy Homeostasis.

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP), a pleiotropic neuropeptide, is widely distributed throughout the body. The abundance of PACAP expression in the central and peripheral nervous systems, and years of accompanying experimental evidence, indicates that PACAP plays crucial roles in diverse biological processes ranging from autonomic regulation to neuroprotection. In addition, PACAP is also abundantly expressed in the hypothalamic areas like the ventromedial and arcuate nuclei (VMN and ARC, respectively), as well as other brain regions such as the nucleus accumbens (NAc), bed nucleus of stria terminalis (BNST), and ventral tegmental area (VTA) - suggesting that PACAP is capable of regulating energy homeostasis via both the homeostatic and hedonic energy balance circuitries. The evidence gathered over the years has increased our appreciation for its function in controlling energy balance. Therefore, this review aims to further probe how the pleiotropic actions of PACAP in regulating energy homeostasis is influenced by sex and dynamic changes in energy status. We start with a general overview of energy homeostasis, and then introduce the integral components of the homeostatic and hedonic energy balance circuitries. Next, we discuss sex differences inherent to the regulation of energy homeostasis via these two circuitries, as well as the activational effects of sex steroid hormones that bring about these intrinsic disparities between males and females. Finally, we explore the multifaceted role of PACAP in regulating homeostatic and hedonic feeding through its actions in regions like the NAc, BNST, and in particular the ARC, VMN and VTA that occur in sex- and energy status-dependent ways.

Nociceptin/orphanin FQ neurons in the Arcuate Nucleus and Ventral Tegmental Area Act via Nociceptin Opioid Peptide Receptor Signaling to Inhibit Proopiomelanocortin and A10 Dopamine Neurons and Thereby Modulate Ingestion of Palatable Food.

The neuropeptide nociceptin/orphanin FQ (N/OFQ) inhibits neuronal activity via its cognate nociceptin opioid peptide (NOP) receptor throughout the peripheral and central nervous systems, including those areas involved in the homeostatic and hedonic regulation of energy homeostasis. We thus tested the hypothesis that N/OFQ neurons in the hypothalamic arcuate nucleus (ARC) and ventral tegmental area (VTA) act via NOP receptor signaling to inhibit nearby anorexigenic proopiomelanocortin (POMC) and A10 dopamine neuronal excitability, respectively, and thereby modulate ingestion of palatable food. Electrophysiologic recordings were performed in slices prepared from transgenic male and ovariectomized (OVX) female N/OFQ-cre/enhanced green fluorescent protein-POMC, N/OFQ-cre and tyrosine hydroxylase-cre animals to see if optogenetically-stimulated peptide release from N/OFQ neurons could directly inhibit these neuronal populations. Binge-feeding behavioral experiments were also conducted where animals were exposed to a high-fat-diet (HFD) for one hour each day for five days and monitored for energy intake. Photostimulation of ARC and VTA N/OFQ neurons produces an outward current in POMC and A10 dopamine neurons receiving input from these cells. This is associated with a hyperpolarization and decreased firing. These features are also sex hormone- and diet-dependent; with estradiol-treated slices from OVX females being less sensitive, and obese males being more sensitive, to N/OFQ. Limited access to HFD causes a dramatic escalation in consumption, such that animals eat 25-45% of their daily intake during that one-hour exposure. Moreover, the NOP receptor-mediated regulation of these energy balance circuits are engaged, as N/OFQ injected directly into the VTA or ARC respectively diminishes or potentiates this binge-like increase in a manner heightened by diet-induced obesity or dampened by estradiol in females. Collectively, these findings provide key support for the idea that N/OFQ regulates appetitive behavior in sex-, site- and diet-specific ways, along with important insights into aberrant patterns of feeding behavior pertinent to the pathogenesis of food addiction.