Mouse Study Sheds Light On Controlling Hunger
February 8, 2012

Mouse Study Sheds Light On Controlling Hunger

Researchers have revealed that the neural circuits controlling hunger and eating behaviors are also controlled by plasticity.

They found that during fasting, the AgRP neurons that drive feeding behaviors actually undergo anatomical changes that cause them to become more active.

This effect results in these neurons "learning" to be more responsive to hunger-promoting neural stimuli.

"The role of plasticity has generally not been evaluated in neuronal circuits that control feeding behavior and with this new discovery we can start to unravel the basic mechanisms underpinning hunger and gain a greater understanding of the factors that influence weight gain and obesity," explained senior author Bradford Lowell, MD, PhD, Professor of Medicine at Harvard Medical School, in a statement.

The root of hunger, eating and weight are based in the brain's complex and rapid-fire neurocircuitry.  Nerve cells containing agouti-related peptide (AgRP) protein and pro-opiomelanocortin (POMC) protein have emerged over the years as critical participants in feeding behaviors.

AgRP neurons, which are located in the brain area that control automatic body functions, have been shown to drive eating and weight gain while POMC neurons inhibit feeding behaviors.

Previous studies on mice showed that when AgRP neurons in the animals are artificially switched off, the animals consume four times more than control animals.

"The 'switched-on' animals search in an unrelenting fashion for food, and when given a task to obtain pellets, will work five times harder to get them," Lowell said.

This study sparked the scientists' interest in understanding the factors that regulate AgRP neuron activity.  The researchers hypothesized that other nerve cells might be behind the regulation.

Neurons communicate with one another through neurotransmitters, which are chemical messengers that traverse synapses.

"Studies in other regions of the brain [for example those controlling learning and reward and addiction behaviors] have demonstrated that glutamate synapses are highly plastic, changing in their strength and sometimes even in their number," explains Lowell.

Synaptic plasticity is brought about when glutamate binds to NMDA receptors on downstream neurons, which exerts powerful control over behavior.

"NMDA receptors are unusual and really interesting," Lowell said in the press release. "When glutamate gets released by upstream neurons and binds to NMDA receptors, calcium enters the downstream neuron.

"This, in turn, engages signal transduction pathways that cause synaptic plasticity. In other parts of the brain, such as the hippocampus, NMDA receptors drive plasticity which serves to encode memories."

In the new research, the team studied mice genetically engineered to lack glutamate-binding NMDA receptors on the AgRP neurons.  They also created mice genetically engineered to lack NMDA receptors on POMC neurons.

The team found that while mice lacking NMDA receptors on POMC neurons showed no change in feeding behavior, mice lacking NMDA receptors on AgRP neurons reacted differently.

"These mice ate a lot less and were much skinnier than a group of control mice," said Lowell. Furthermore, the scientists found that a 24-hour period of fasting — which causes intense hunger in the control mice — was associated with a 67 percent increase in the number of dendritic spines on the AgRP neurons.

Coauthor Bernardo Sabatini of the Harvard Medical School said he was also shocked about the results.

"I've been studying spines for a long time and I've never before seen a manipulation that triggered such rapid and robust changes in spine number," Sabatini said in a press release.

"Clearly, feeding is plugging in to the most basic mechanisms that control synapse and spine number in these cells. This may be a great system to understand not only feeding behavior, but also to understand the cell biology behind dynamic synapse formation and retraction."

When the control mice were re-fed, the number of spines dropped back to normal.  Lowell said these changes in spine number in mice lacking NMDA receptors on the downstream AgRP neurons suggests that structural plasticity of excitatory glutamate synapses on AgRP neurons is an important regulator of feeding behavior.

The study will be published in the journal Neuron on February 9, 2012.


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