Mapping excessive "disgust" in the brain: Ventral pallidum inactivation recruits distributed circuitry to make sweetness "disgusting".

The ventral pallidum (VP) is an important structure in processing reward. The VP may be the only brain structure where localized lesions in rats replace normal facial "liking" expressions to sweetness with excessive "disgust" reactions, such as gapes and chin rubs, that are normally reserved for unpalatable tastes. The posterior half of the VP (pVP) contains a hedonic hot spot where opioid or related neurochemical stimulations can amplify positive "liking" reactions to sweet taste. This is the same site where lesions or pharmacological inactivations replace positive hedonic reactions to sucrose with intense negative "disgust." In the present study, we aimed to identify brain networks recruited by pVP inactivation to generate excessive "disgust," using neuronal Fos expression as a marker of neurobiological activation. Microinjections in pVP of inhibitory GABAA/B agonists (muscimol and baclofen) caused rats to exhibit excessive "disgust" reactions to sucrose. Excessive "disgust" was accompanied by recruitment of neural Fos activation in several subcortical structures, including the posterior medial shell of nucleus accumbens (which also contains another GABAergic "disgust"-inducing "hedonic cold spot"), the bed nucleus of stria terminalis, lateral habenula, hypothalamus, and midbrain ventral tegmentum. Fos suppression was found in cortical limbic regions, including previously identified hedonic hot spots in the anteromedial orbitofrontal cortex and posterior insula. Finally, in addition to inducing excessive "disgust," pVP inactivation abolished motivational "wanting" to eat palatable food, reduced positive social interactions, and reordered sensorimotor relations. Our findings identify potential "disgust" generators in the brain that are released into excitation by pVP inhibition and may serve as targets for future research.

Optogenetic mapping of feeding and self-stimulation within the lateral hypothalamus of the rat.

The lateral hypothalamus (LH) includes several anatomical subregions involved in eating and reward motivation. This study explored localization of function across different LH subregions in controlling food intake stimulated by optogenetic channelrhodopsin excitation, and in supporting laser self-stimulation. We particularly compared the tuberal LH subregion, the posterior LH subregion, and the lateral preoptic area. Local diameters of tissue optogenetically stimulated within the LH were assessed by measuring laser-induced Fos plumes and Jun plumes via immunofluorescence surrounding optic fiber tips. Those plume diameters were used to map localization of function for behavioral effects elicited by LH optogenetic stimulation. Optogenetic stimulation of the tuberal subsection of the LH produced the most robust eating behavior and food intake initially, but produced only mild laser self-stimulation in the same rats. However, after repeated exposures to optogenetic stimulation, tuberal LH behavioral profiles shifted toward more self-stimulation and less food intake. By contrast, stimulation of the lateral preoptic area produced relatively little food intake or self-stimulation, either initially or after extended stimulation experience. Stimulation in the posterior LH subregion supported moderate self-stimulation, but not food intake, and at higher laser intensity shifted valence to evoke escape behaviors. We conclude that the tuberal LH subregion may best mediate stimulation-bound increases in food intake stimulated by optogenetic excitation. However, incentive motivational effects of tuberal LH stimulation may shift toward self-stimulation behavior after repeated stimulation. By contrast, the lateral preoptic area and posterior LH do not as readily elicit either eating behavior or laser self-stimulation, and may be more prone to higher-intensity aversive effects.

Direct hypothalamic and indirect trans-pallidal, trans-thalamic, or trans-septal control of accumbens signaling and their roles in food intake.

Due in part to the increasing incidence of obesity in developed nations, recent research aims to elucidate neural circuits that motivate humans to overeat. Earlier research has described how the nucleus accumbens shell (AcbSh) motivates organisms to feed by activating neuronal populations in the lateral hypothalamus (LH). However, more recent research suggests that the LH may in turn communicate with the AcbSh, both directly and indirectly, to re-tune the motivation to consume foods with homeostatic and food-related sensory signals. Here, we discuss the functional and anatomical evidence for an LH to AcbSh connection and its role in eating behaviors. The LH appears to modulate Acb activity directly, using neurotransmitters such as hypocretin/orexin or melanin concentrating hormone (MCH). The LH also indirectly regulates AcbSh activity through certain subcortical "relay" regions, such as the lateral septum (LS), ventral pallidum (VP), and paraventricular thalamus, using a variety of neurotransmitters. This review aims to summarize studies on these topics and outline a model by which LH circuits processing energy balance can modulate AcbSh neural activity to regulate feeding behavior.

Ipsilateral feeding-specific circuits between the nucleus accumbens shell and the lateral hypothalamus: regulation by glutamate and GABA receptor subtypes.

The nucleus accumbens shell (AcbSh) and the lateral hypothalamus (LH) are both involved in the control of food intake. Activation of GABA(A) receptors or blockade of AMPA and kainate receptors within the AcbSh induces feeding, as does blockade of GABA(A) receptors or activation of NMDA receptors in the LH. Further, evidence suggests that feeding induced via the AcbSh can be suppressed by LH inhibition. However, it is unclear if this suppression is specific to feeding. Adult male Sprague-Dawley rats with 3 intracranial guide cannulas, one unilaterally into the AcbSh and two bilaterally into the LH, were used to explore this issue. DNQX (1.25 µg) or muscimol (100 ng) infused into the AcbSh unilaterally elicited feeding, and this elicited intake was suppressed by bilateral LH injection of d-AP5 (2 µg) or muscimol (25 ng). The effectiveness of d-AP5 or muscimol infusion into either the LH site ipsilateral or contralateral to the AcbSh injection was compared. Ipsilateral LH injection of d-AP5 or muscimol was significantly more effective than contralateral injection in suppressing food intake initiated by AcbSh injection of DNQX or muscimol. These results add to the prior evidence that inhibition of the LH through pharmacological modulation of NMDA or GABA(A) receptors specifically suppresses feeding initiated by AcbSh inhibition, and that these two regions communicate via an ipsilateral circuit to specifically regulate feeding.

Behaviorally specific versus non-specific suppression of accumbens shell-mediated feeding by ipsilateral versus bilateral inhibition of the lateral hypothalamus.

The nucleus accumbens shell (AcbSh) and lateral hypothalamus (LH) are linked in the control of food intake. Pharmacological inhibition of the LH may block AcbSh-elicited feeding, but the behavioral phenotype associated with this feeding suppression is unknown. To examine this phenotype, adult male Sprague-Dawley rats were implanted with three cannulas - one unilaterally in the AcbSh and two bilaterally in the LH - to allow for central drug injections. The AcbSh received injections of the AMPA receptor antagonist DNQX or the GABAA receptor agonist muscimol, while the LH received injections of the NMDA receptor antagonist D-AP5 or muscimol. Eating, drinking, grooming, locomotion, quiescence, and sleeping behaviors were measured every minute for 60 min post-injection. From these observational data, feeding bout durations, feeding frequency, and latency to feed were determined. AcbSh muscimol or DNQX increased food intake by increasing feeding bout durations and frequency and decreasing latency to feed. D-AP5 or muscimol, injected into the LH bilaterally or ipsilateral to the AcbSh injection, reversed these AcbSh-mediated effects. Though bilateral LH D-AP5 or muscimol injections blocked feeding responses, they also hastened onset of sleep. In contrast, ipsilateral LH D-AP5 or muscimol injections suppressed AcbSh-mediated feeding behaviors without substantially altering sleeping or other behaviors. These results suggest bilateral LH inhibition via NMDA receptor blockade or GABAA receptor activation produces behavioral effects that might indirectly suppress feeding, but ipsilateral LH inhibition through these receptors suppresses AcbSh AMPA and GABAA receptor-mediated feeding specifically. This evidence strengthens the concept of a feeding-specific association between these regions.