Hedonic over-consumption contributing to obesity involves altered activation within the mesolimbic dopamine system. Dysregulation of dopamine signaling in the nucleus accumbens shell (NAS) has been implicated in reward-seeking behaviors, such as binge eating, which contributes to treatment resistance in obesity (Wise, 2012). Direct modulation of the NAS with deep brain stimulation (DBS), a surgical procedure currently under investigation in humans for the treatment of major depression, obsessive-compulsive disorder, and addiction, may also be effective in ameliorating binge eating. Therefore, we examined the ability of DBS of the NAS to block this behavior in mice. c-Fos immunoreactivity was assessed as a marker of DBS-mediated neuronal activation. NAS DBS was found to reduce binge eating, and increased c-Fos levels in this region. DBS of the dorsal striatum had no influence on this behavior, demonstrating anatomical specificity for this effect. The dopamine D2 receptor antagonist, raclopride, attenuated the action of DBS, while the D1 receptor antagonist, SCH-23390, was ineffective, suggesting that dopamine signaling involving D2 receptors underlies the effect of NAS DBS. To determine the potential translational relevance to the obese state, chronic NAS DBS was also examined in diet-induced obese mice, and was found to acutely reduce caloric intake and induce weight loss. Taken together, these findings support the involvement of the mesolimbic dopamine pathways in the hedonic mechanisms contributing to obesity, and the efficacy of NAS DBS to modulate this system.

Trace conditioning, a form of classical conditioning in which the presentation of the conditioned stimulus (CS) and the unconditioned stimulus (US) is separated in time by an interstimulus interval, requires an intact hippocampus. In contrast, classical conditioning procedures in which the CS and US are not separated by an interstimulus interval (i.e., delay conditioning procedures) typically do not (Solomon et al., 1986). However, why trace conditioning is dependent on the hippocampus is unknown. Several theories suggest that it is specifically the discontiguity between the CS and US in trace conditioning that critically engages the hippocampus. However, there are other explanations that do not depend on discontiguity. To determine whether the lack of contiguity renders trace conditioning hippocampal dependent, we designed a "contiguous trace conditioning" (CTC) paradigm in which CS-US contiguity is restored by representing the CS simultaneously with the US. Although rats with excitotoxic lesions of the hippocampus could not learn a standard trace fear-conditioning paradigm, lesioned rats trained on CTC showed significant conditioning, at levels similar to those with sham surgeries. Importantly, lesioned rats trained solely with simultaneous CS-US presentations did not demonstrate conditioning. Together, these data suggest that rats with hippocampal lesions can form a memory of a trace CS-US association when contiguity is restored. Therefore, the dependence of traditional trace paradigms on the hippocampus can be attributed to the absence of temporal contiguity.

Santollo J, Wiley MD, Eckel LA. Acute activation of ER␣ decreases food intake, meal size, and body weight in ovariectomized rats. Am J Physiol Regul Integr Comp Physiol 293: R2194-R2201, 2007. First published October 17, 2007; doi:10.1152/ajpregu.00385.2007.-Estradiol exerts many of its actions by coupling with two nuclear estrogen receptor (ER) proteins, ER␣, and ER␤.While the acute, anorexigenic effect of estradiol appears to involve such a mechanism, the relative contributions of ER␣ and ER␤ are equivocal. To address this problem, food intake was monitored in ovariectomized (OVX) rats following acute administration of a selective ER␣ agonist (4,4Ј,4ЈЈ-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol, PPT; dose range ϭ 0 -200 g), a selective ER␤ agonist (2,3-bis(4-hydroxyphenyl)-propionitrile, DPN; dose range ϭ 0 -600 g), and a physiological (4 g) dose of estradiol benzoate (EB). While PPT-treated rats displayed dosedependent decreases in daily food intake and body weight, neither of these measures was influenced by any dose of DPN. In addition, DPN failed to modulate the anorexigenic effect of PPT when the two ER agonists were coadministered. Meal pattern analysis revealed that the anorexigenic effect of 75 g PPT (a dose of PPT that produced a similar decrease in daily food intake as 4 g EB) was mediated by a decrease in meal size, not meal number. Thus, PPT, like EB and endogenous estradiol, decreases food intake by selectively affecting the controls of meal size. The finding that acute administration of 75 g PPT failed to induce a conditioned taste aversion suggests that the anorexigenic effect of this dose of PPT is not secondary to malaise. Taken together, our findings demonstrate that selective activation of ER␣ decreases food intake, body weight, and meal size in the ovariectomized rat. 4,4Ј,4ЈЈ-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol; 2,3-bis(4-hydroxyphenyl)-propionitrile; food intake; estradiol THE OVARIAN HORMONE ESTRADIOL exerts an inhibitory effect on food intake that is particularly well characterized in the rat. For example, the periovulatory increase in estradiol secretion in female rats is associated with a phasic decrease in food intake during estrus (4,8,12), and bilateral ovariectomy promotes sustained hyperphagia (33). Available data involving estradiol benzoate (EB) or progesterone replacement alone and in combination provide evidence that the hyperphagia displayed by ovariectomized (OVX) rats is mediated solely by the postsurgical decline in estradiol secretion (2, 17).Food intake is defined by the product of meal size and meal number over a given period of time. Accordingly, any change in food intake must involve a change in one or both of these parameters. Because meal size and meal number are independently controlled in the rat (32), an important first step in identifying the mechanism underlying estradiol's anorexigenic effect involved a detailed analysis of the spontaneous feeding patterns of cycling and EB-treated OVX rats. Such studies revealed that estradiol decreases food ...

Estradiol (E2) exerts an inhibitory effect on food intake in a variety of species. While compelling evidence indicates that central, rather than peripheral, estrogen receptors (ERs) mediate this effect, the exact brain regions involved have yet to be conclusively identified. In order to identify brain regions that are sufficient for E2's anorectic effect, food intake was monitored for 48 h following acute, unilateral, microinfusions of vehicle and two doses (0.25 and 2.5 μg) of a water-soluble form of E2 in multiple brain regions within the hypothalamus and midbrain of ovariectomized rats. Dose-related decreases in 24-h food intake were observed following E2 administration in the medial preoptic area (MPOA), arcuate nucleus (ARC), and dorsal raphe nucleus (DRN). Within the former two brain areas, the larger dose of E2 also decreased 4-h food intake. Food intake was not influenced, however, by similar E2 administration in the paraventricular nucleus, lateral hypothalamus, or ventromedial nucleus. These data suggest that E2-responsive neurons within the MPOA, ARC, and DRN participate in the estrogenic control of food intake and provide specific brain areas for future investigations of the cellular mechanism underlying estradiol's anorexigenic effect.

Available data suggest that estradiol exerts an inhibitory effect on food intake by modulating the actions of multiple gut- and brain-derived peptides implicated in the control of food intake. For example, recent studies have shown that estradiol decreases the orexigenic effects of ghrelin and melanin-concentrating hormone. In the present study, we examined estradiol's ability to decrease the actions of two additional orexigenic peptides, neuropeptide Y (NPY) and agouti-related protein (AgRP). Food intake was monitored following lateral ventricular infusions of 5 microg NPY, 10 microg AgRP, or saline vehicle in ovariectomized rats treated with either 1 microg estradiol or sesame oil vehicle. NPY increased food intake for 2h in both oil- and estradiol-treated ovariectomized rats. During this interval, the orexigenic effect of NPY was significantly greater in oil-treated rats, relative to estradiol-treated rats. In contrast to the short-term action of NPY, a single injection of AgRP increased food intake for 3 days in oil- and estradiol-treated rats. Meal pattern analysis revealed that the orexigenic effect of AgRP is mediated by an increase in meal size, not meal number. Unlike that observed following NPY treatment, estradiol failed to modulate the magnitude by which AgRP increased food intake and meal size. We conclude that a physiological regimen of estradiol treatment decreases the orexigenic effect of NPY, but not AgRP, in ovariectomized rats.