Cortical Manipulation of Appetite

The impetus to eat is crucial to an animal’s survivability. However in today’s fast paced society, we do not think twice about our meals and even less about our appetite, the primary stimulus for eating. The science behind appetite has been profound in providing us with various mechanisms and pathways through which we may modulate desire to eat. Having the ability to influence appetite may play a powerful role in treating disorders such as polyphagia and anorexia.

According to the National Association of Anorexia Nervosa and Associated Disorders (ANAD), approximately twenty four million Americans suffer from some type of eating disorder. The National Institute of Mental Health places 4% of all adults and 2.7% of children at risk of anorexia, bulimia, or binge-eating disorder. Currently, the popular treatments of such disorders are mainly psychotherapy and antidepressant medications. While effective, these treatments do not completely solve the problem and for those who did not find the treatments helpful, the alternatives are bleak. Recent research on pathways that target the brain directly may be of more promise.

Although various brain regions and compounds are implicated in the central control of appetite, there still remain unknown circuits and modulatory pathways. Compounds that are used in transmitting appetite information include ghrelin, orexins, and leptin [1]. Commonly mentioned areas in the brain include the hypothalamus, the main regulatory organ for human appetite, and the nucleus accumbens, an area that manages neurotransmitters, opioids, and endocannabinoids to affect appetite.

The endocannabinoid system is a system of neuromodulatory receptors and corresponding neurotransmitter lipids in the brain that is a critical component of central regulation of homeostatsis [2]. The receptors of the endocannabinoid system are the CB1, CB2, and two G protein-coupled receptors. Recently, it was found that lack of CB1 receptors decreased food intake and may be linked to alteration of sensory perception [3].

Moreover the prefrontal cortex (PFC), commonly associated with decision making, was also found to be involved with regulation of appetite [4]. Although experiments with lesions of PFC did not provide conclusive results, the prefrontal dopamine system presents a viable option to explore. Midbrain dopaminergic neurons play important roles in food intake, with animals devoid of dopamine becoming hypophagic and dying of starvation [5]. Dopamine is a neurotransmitter that is mainly linked with roles in motivation, reward, and pleasantness. Although there are also dopaminergic neurons in the PFC, the pathway between direct stimulation of the PFC on feeding remains unknown.

The following papers delve into and attempt to fill the gaps between the endocannabinoids in olfactory sensory appetite and dopaminergic receptors in PFC on feeding.  CB1 and D1 receptors specifically target the olfactory system and PFC, respectively.

Dopamine effect on feeding behavior

In one study led by researchers, the experimenters sought to explore the role of dopamine neurons (D1) in the prefrontal cortex in food intake [6]. They tested the medial prefrontal cortex (mPFC) because it was shown to be highly expressive of D1 receptors and have functional roles in hunger-related behavior [7].

The experiment consisted of two groups of mice. One group was fed normally while the other was food-deprived for 24 hours and then allowed to eat; the amount of pellets eaten was recorded over a period of 90 min. The food deprived group ate six times more than the control and also expressed a higher expression of D1 in dopaminergic neurons.

Knowing that the expression of D1 seems to positively correlate with food intake, the authors next tested whether the stimulation of D1 neurons can impact food intake. The experimenters introduced a light-sensitive protein in the D1 neurons that allowed for the selective activation of such neurons; the control, naturally, had no such protein. Subsequently, they found that mice stimulated at 20Hz ate significantly more pellets than control mice, but no difference was found when mice were stimulated with 5Hz, suggesting that higher activity has a greater effect. Following this, an inhibitory light-sensitive protein was expressed in mice. During feeding, both experimental and control mice were stimulated with 20Hz light; the experimental mice were found to consume fewer pellets than the control. This suggests that inhibition of D1 neurons can decrease food intake.

Next, the authors searched for downstream targets of D1 neurons to look for more sites of modulation. To do this, the authors used an axon-staining protein and traced the D1 axonal targets. They found D1 neurons projected to several downstream targets with the most important being the caudal-medial basolateral nuclei of the amygdala (mBLA). The mBLA was then introduced with inhibitory and excitatory light proteins and stimulated to determine effect on food intake via light stimulation. As with the D1 neurons, stimulation of mBLA led to increased feeding while inhibition decreased feeding. This result indicates that food-intake can be modulated at multiple points along this pathway and is not restricted to one section.

Endocannabinoid effect on feeding behavior

A paper published in 2014 titled “The endocannabinoid system controls food intake via olfactory processes” sought to unite the endocannabinoid effect on olfactory perception and food intake [8]. While the paper mainly focused on linking food intake and sensory perception, it provides evidence of the modulatory effects of the endocannabinoid system on food intake.

Because they were mainly interested in the CB1 receptor, mutant mice lacking CB1 receptors in several locations in the neocortex (Glu-CB1-/-) were used. They found that Glu-CB1-/- mice had negligible differences in CB1 expression in many regions except the main olfactory bulb (MOB). After a 24 hour fast, the Glu-CB1-/- mice displayed an increase in food intake compared to control mice. This suggests the presence of CB1 may attenuate fasting-induced food intake in mice.

It is known that a 24 hour fast in mice increases the levels of endocannabinoid anandamide (a neurotransmitter) in the hypothalamus [9]. It is no surprise when the authors found that AEA was also increased in the MOB of fasted mice. Naturally, they then introduced a CB1 receptor inhibitor into the MOB before re-feeding, resulting in drastically reduced food intake. This suggests that CB1 receptor activation is essential for fasting-induced food intake.

The authors then tested to identify whether the endocannabinoid system in MOB manipulate food intake through influencing glutamine sensitive neurons. A local infusion of NMDA receptor (a glutamine receptor) inhibitor was given to control and Glu-CB1-/- mice. The mutant mice was found to eat less than control mice, suggesting the phenotype is caused by excessive glutamatergic signaling in the MOB. Thus, these data imply that feeding regulation after fasting involves a decrease in glutamergic signaling in the MOB, regulated by CB1 receptors.

To determine if CB1 is sufficient for the increased food intake in fasted mice, the authors rescued the CB1 deficient phenotype Glu-CB1-/- mice using Cre-Lox recombination, which reinserted the CB1 receptor gene into the neurons. Through the use of immunohistochemical techniques, the rescued mice (Glu-CB1-RS) mice was found to express CB1 receptors in glutamine sensitive neurons and was indistinguishable from wild-type mice. Furthermore, the rescued mice’s food intake was not significantly different from control.

Though both papers delved into different pathways affecting appetite, they opened up new avenues for the exploration of additional treatments for eating disorders. The first paper described how the prefrontal cortex is able to influence appetite and food intake through the influence of dopamine sensitive neurons. This is interesting because the prefrontal cortex, notable for its role in planning motor functions, is now involved in desire to eat. Its downstream targets involve parts of the limbic system, most notably the amygdala which has a role in memory processing and emotional reactions. The effects of the D1 neurons are not spontaneous; instead it was a gradual change that promoted additional intake when sated. This study was significant because it identified a new top down circuitry related to feeding. The mechanism by which the prefrontal cortex modifies food intake relies upon dopamine, the “feel good” compound. Of course, currently dopamine is targeted in eating disorder treatments in the form of antidepressants, especially the dopamine reuptake inhibitors that extend the duration of dopamine release. Now that the pathway is clearer, a more specific treatment may include medication to specifically target D1 neurons in the prefrontal cortex or target the amygdala without affecting the dopamine system.

However, it does not provide a complete picture of the pathway. The second paper found that the CB1 receptor regulates activity in MOB by inhibiting excitatory projections in the MOB and increasing feeding behavior. This indicates that through inhibitory actions, the CB1 receptors can increase the amount of food intake. This presents another opportunistic treatment such that a medication specifically targeting the CB1 receptors may change food intake.

To further explore the entire pathway, the relationship between opioid receptors and D1 needs to be clarified. Discovering the role of endocannabinoids on dopamine release may help solidify the picture. Though no complete picture of the feeding mechanisms was provided for the two papers, the results of the two provided a powerful foundation to manipulate feeding behavior. That dopamine sensitive neurons increase food intake when sated renders them a prime target to help those suffering from anorexia nervosa. The endocannabinoids receptors, on the other hand, decrease food intake when inhibited, and thus acting as a potential treatment for binge-eating disorder.

 

References

[1] Julliard AK, et al (2007) Changes in rat olfactory detection performance induced by orexin and leptin mimicking fasting and satiation. Behav Brain Res. 183:123-129.

[2] DiPatrizio N.V.  &  Piomelli D. (2012) The  thrifty lipids:  endocannabinoids  and  the  neural control  of  energy  conservation. Trends  Neurosci. 35:403–411 .

[3] Bellocchio L., et al. (2010) Bimodal control of stimulated food intake by the endocannabinoid system. Nat.  Neurosci. 13:281–283.

[4] Miller E.K. & Cohen J.D. (2001) An integrative theory of prefrontal cortex function. Annu. Rev.  Neurosci. 24:167–202.

[5] Hnasko T.S., Sotak B.N. & Palmiter R.D. (2005) Morphine reward in dopamine-deficient mice. Nature 438:854–857.

[6] Land B.B., et al. (2014) Medial prefrontal D1 dopamine neurons control food intake. Nature Neuroscience. 17:248-253.

[7] Nair S.G. et  al. (2011) Role  of  dorsal  medial  prefrontal  cortex  dopamine  D1-family receptors  in  relapse  to  high-fat  food  seeking  induced  by  the  anxiogenic  drug yohimbine. Neuropsychopharmacology 36:497–510.

[8] Soria-Gomez E., et al. (2014) The endocannabinoid system controls food intake via olfactory processes. Nature Neuroscience. 17:407-415.

[9] Di  Marzo,  V. et  al. (2001) Leptin-regulated  endocannabinoids  are  involved  in  maintaining food  intake. Nature 410:822–825.

 

Bohan Xing is an undergraduate student at Northwestern University. Follow The Triple Helix Online on Twitter and join us on Facebook.

 

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