Described in the February 9, 2012 issue of the journal Neuron,<\/em> the findings show that during fasting, the AgRP neurons that drive feeding behaviors actually undergo anatomical changes that cause them to become more active, which results in their \u201clearning\u201d to be more responsive to hunger-promoting neural stimuli<\/strong>.<\/p>\n \u201cThe 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,\u201d explains senior author Bradford Lowell, MD, PhD, an investigator in BIDMC\u2019s Division of Endocrinology, Diabetes and Metabolism and Professor of Medicine at Harvard Medical School (HMS).<\/p>\n Adds BIDMC Chairman of Neurology Clifford Saper, MD, PhD, \u201cFor most animals, finding enough food to survive is their biggest daily challenge, and so the brain\u2019s increase in feeding drive may be adaptive. But, for humans who are overweight, reducing this drive to the AgRP neurons may prove to be a path to future weight loss therapies.\u201d<\/p>\n The roots of hunger, eating, and weight are based in the brain\u2019s complex and rapid-fire neurocircuitry. Over the years, nerve cells containing agouti-related peptide (AgRP) protein and pro-opiomelanocortin (POMC) protein have emerged as critical players in feeding behaviors. Located in the hypothalamus, the brain area that controls automatic body functions, AgRP neurons have been shown to drive eating and weight gain while POMC neurons inhibit feeding behaviors, causing satiety and weight loss.<\/p>\n Previous work by the Lowell lab and others had demonstrated that when AgRP neurons in mice are artificially switched on, the animals eat voraciously, consuming four times more than control animals. \u201cThe \u2018switched-on\u2019 animals search in an unrelenting fashion for food, and when given a task to obtain pellets, will work five times harder to get them,\u201d Lowell explains. \u201cGiven the important role played by AgRP neurons, we had a great interest in understanding the factors that regulate their activity.\u201d While much focus had centered on hormones, including leptin, insulin and ghrelin, the Lowell team hypothesized that other nerve cells might be the mechanisms that were regulating neuronal activity.<\/p>\n Neurons communicate with one another via neurotransmitters, chemical messengers that traverse synapses, the specialized junctions between upstream and downstream neurons. Glutamate is one such excitatory neurotransmitter.<\/p>\n \u201cStudies 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,\u201d explains Lowell. Shown to exert powerful control over behavior, synaptic plasticity is brought about when glutamate binds to NMDA receptors on downstream neurons.<\/p>\n \u201cNMDA receptors are unusual and really interesting,\u201d he adds. \u201cWhen 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.\u201d<\/p>\n Led by co-first authors Tiemin Liu, PhD, Dong Kong, PhD, Bhavik P. Shah, PhD, and Chianping Ye, PhD, the investigators created and studied mice genetically engineered to lack glutamate-binding NMDA receptors on the AgRP neurons. For the sake of comparison, they also created mice genetically engineered to lack NMDA receptors on POMC neurons.<\/p>\n They found that while mice lacking NMDA receptors on POMC neurons showed no change in feeding behavior, the situation was dramatically different in the mice lacking NMDA receptors on AgRP neurons. \u201cThese mice ate a lot less and were much skinnier than a group of control mice,\u201d explains Lowell. Furthermore, the scientists found that a 24-hour period of fasting \u2013 which causes intense hunger in the control mice \u2013 was associated with a 67 percent increase in the number of dendritic spines on the AgRP neurons.<\/p>\n \u201cDendritic spines are tiny structures attached to the neuron\u2019s dendrites, the tree-like branches that receive incoming signals from upstream neurons,\u201d explains Lowell. \u201cThese structures are the physical site, the subcellular communication hub, where synaptic input from upstream glutamate-releasing neurons is received, typically one synaptic input per spine.\u201d<\/p>\n \u201cI\u2019ve been studying spines for a long time and I\u2019ve never before seen a manipulation that triggered such rapid and robust changes in spine number,\u201d says coauthor Bernardo Sabatini, MD, PhD, a Howard Hughes Medical Institute investigator in the Department of Neurobiology at Harvard Medical School. \u201cClearly, 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.\u201d<\/p>\n When the control mice were refed \u2013 and their hunger alleviated \u2013 the number of spines dropped back to normal. (In contrast, fasting had no effect on spine number in the mutant mice lacking NMDA receptors on AgRP neurons.) These dramatic changes in spine number and their tight association with states of hunger and satiety in control mice \u2013 and the absence of changes in spine number in mice lacking NMDA receptors on the downstream AgRP neurons\u2013 strongly suggests that structural plasticity of excitatory glutamate synapses on AgRP neurons is an important regulator of feeding behavior<\/strong>, says Lowell.<\/p>\n \u201cObesity is a major risk factor for type 2 diabetes, cardiovascular disease, and certain types of cancer,\u201d he adds. \u201cBy understanding the neurobiological mechanisms underlying feeding behaviors, we can work on treatments for a problem that has now become a global epidemic. These findings move us closer to a mechanistic understanding of how various factors controlling hunger might work.\u201d<\/p>\n This study was supported by grants from the National Institutes of Health and the American Diabetes Association, as well as support from the Shapiro Predoctoral Fellowship and the Parkinson\u2019s Disease Foundation Postdoctoral fellowship programs.<\/p>\n In addition to Lowell, Sabatini and the paper\u2019s first authors, other coauthors include BIDMC investigators Shuichi Koda and Zongfang Yang and HMS investigators Arpiar Saunders and Jun B. Ding.<\/p><\/blockquote>\n","protected":false},"excerpt":{"rendered":" From the Beth Israel Deaconess Medical Center press release: Synaptic plasticity \u2013 the ability of the synaptic connections between the brain\u2019s neurons to change and modify over time — has… Read more »<\/a><\/p>\n","protected":false},"author":4,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[10,6],"tags":[42,134,208,155,141],"_links":{"self":[{"href":"https:\/\/therapytoronto.ca\/news\/wp-json\/wp\/v2\/posts\/1255"}],"collection":[{"href":"https:\/\/therapytoronto.ca\/news\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/therapytoronto.ca\/news\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/therapytoronto.ca\/news\/wp-json\/wp\/v2\/users\/4"}],"replies":[{"embeddable":true,"href":"https:\/\/therapytoronto.ca\/news\/wp-json\/wp\/v2\/comments?post=1255"}],"version-history":[{"count":2,"href":"https:\/\/therapytoronto.ca\/news\/wp-json\/wp\/v2\/posts\/1255\/revisions"}],"predecessor-version":[{"id":1257,"href":"https:\/\/therapytoronto.ca\/news\/wp-json\/wp\/v2\/posts\/1255\/revisions\/1257"}],"wp:attachment":[{"href":"https:\/\/therapytoronto.ca\/news\/wp-json\/wp\/v2\/media?parent=1255"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/therapytoronto.ca\/news\/wp-json\/wp\/v2\/categories?post=1255"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/therapytoronto.ca\/news\/wp-json\/wp\/v2\/tags?post=1255"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}![\"\"](\"http:\/\/therapytoronto.ca\/images\/blogpics\/Mice.jpg\" "\\"mice\\"")
Synaptic plasticity \u2013 the ability of the synaptic connections between the brain\u2019s neurons to change and modify over time — has been shown to be a key to memory formation and the acquisition of new learning behaviors.<\/strong> Now research led by a scientific team at Beth Israel Deaconess Medical Center (BIDMC) reveals that the neural circuits controlling hunger and eating behaviors are also controlled by plasticity<\/strong>.<\/p>\n