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Pathways Of Motivational Pathways Mapped Through the Brain By Optogenetics

Whether you are an apple tree or an antelope, survival depends on using your energy efficiently. In a difficult or dangerous situation, the key question is whether exerting effort - sending out roots in search of nutrients in a drought or running at top speed from a predator - will be worth the energy.
In a paper published online in Nature, Karl Deisseroth, MD, PhD, a professor of bioengineering and of psychiatry and behavioral sciences at Stanford University, and postdoctoral scholar Melissa Warden, PhD, describe how they have isolated the neurons that carry these split-second decisions to act from the higher brain to the brain stem. In doing so, they have provided insight into the causes of severe brain disorders such as depression.


In organisms as complex as humans, the neural mechanisms that help answer the question, "Is it worth my effort?" can fail, leading to debilitating mental illnesses. Major depressive disorder, for instance, which affects nearly 20 percent of people at some point in life, is correlated with underperformance in the parts of the brain involved in motivation. But researchers have struggled to work out the exact cause and effect.
"It's challenging because we do not have a fundamental understanding of the circuitry that controls this sort of behavioral pattern selection. We don't understand what the brain is doing wrong when these behaviors become dysfunctional, or even what the brain is supposed to be doing when things are working right," Deisseroth said. "This is the level of the mystery we face in this field."
Clinicians refer to this slowing down of motivation in depressed patients as "psychomotor retardation." According to Deisseroth, who is also a practicing psychiatrist, patients may experience this symptom mentally, finding it hard to envision the positive results of an action, or, he said, they may feel physically heavy, like their limbs just do not want to move.
"This is one of the most debilitating aspects of depression, and motivation to take action is something that we can model in animals. That's the exciting opportunity for us as researchers," said Deisseroth, who also holds the D.H. Chen Professorship.
Light coercion
Psychiatrists, Deisseroth included, believe the will to act may be born in the prefrontal cortex - the foremost part of the brain that helps plan and coordinate action. It then zips through the brain as a series of electrical signals, passing from neuron to neuron along countless branching pathways until it reaches the nerves that directly implement movement. Until this study, however, it was not clear which of these pathways might control the willingness to meet challenges, or the anticipation that action might be worthwhile in a difficult situation.
To isolate these pathways relevant to depression, Deisseroth's team needed to stimulate specific brain cells in rodents and observe changes in their behavior. They used optogenetics, a technique Deisseroth developed at Stanford in 2005, which has since revolutionized the fields of bioengineering and neuroscience.
The secret is as old as green algae. These single-celled organisms produce a protein called channelrhodopsin that makes them sensitive to sunlight. Borrowing and engineering the gene for this protein, Deisseroth has been able to create neurons that respond to light delivered from fiber-optic cables. He can turn the neurons on and off by sending bursts of light to activate different areas of the brain and then observe the effects on behavior.
Working backward
Surprisingly, the researchers found that simply stimulating the prefrontal cortices of rodents didn't motivate them to try any harder in a laboratory challenge. It turns out that motivation is not as simple as stimulating a region of the brain. Instead of one switch in the prefrontal cortex that turns motivation on, multiple switches work in concert. Some neurons excite motivated activity and others inhibit it. Broadly stimulating the executive part of the brain will not generate a simple effect on behavior.
"It's one step more subtle" said Deisseroth, "but this is something that optogenetics was very well-suited to resolve."
An optogenetic method called projection targeting allowed the scientists to work backward from the brain stem and find the exact pathway from neurons in the prefrontal cortex that signal motivation.
The researchers first introduced their light-sensitive protein into cells in the prefrontal cortex. The light sensitivity then spread out like the branches of a tree through all the outgoing connections and eventually made its way to the brain stem, making those regions light sensitive, too.
Then, illuminating the newly light-sensitive regions of the brain stem thought to control motivational movement, Deisseroth and Warden watched the behavioral effects as a subgroup of neurons in the prefrontal cortex that sent connections to brain stem were activated. They could see not only which cells are possibly involved in motivation, but the way motivation moves from one brain region to another.
Mapping motivation
The researchers suspected that one part of the brain stem in particular, the dorsal raphe nucleus, might be crucial to behaviors that control effort. This cluster of cells is a production hub for serotonin - a chemical messenger that changes the firing behavior of other cells. Serotonin is associated with mood modulation; many antidepressant drugs, for instance, may act by increasing serotonin concentration in the brain.
When the pathway between the prefrontal cortex and the dorsal raphe nucleus was stimulated, rodents facing a challenge in the lab showed an immediate and dramatic surge in motivation.
Curiously, however, when the rodents were relaxing in their home environment, the same stimulation had no effect. The pathway was not merely linked to any action, or to agitation; it was, more specifically, helping to "set the effort that the organism was willing to put forth to meet a challenge," Deisseroth said.
Researchers were also able to produce the opposite effect - reduced effort in response to challenge - by stimulating prefrontal neurons that project to the lateral habenula, a region perched atop the brain stem that is thought to play a role in depression. When this region was getting signals driven optogenetically from the prefrontal cortex, rodents put forward less effort.
Larger puzzles
These findings are part of a larger puzzle that Deisseroth and his team have pieced together by using optogenetics to model human behavior in animal subjects. The work has already helped clinicians and researchers to better understand what is going on in a patient's brain.
Connecting depressive symptoms with brain pathways may be helpful in the development of drugs, but according to Deisseroth, the most important part of this research is its insight into how motivation works in both depressed and healthy people.
He has observed that this insight alone can be helpful to those dealing with mental illness and seeking an explanation for troubling symptoms that feel deeply personal. For those patients, he said, simply knowing that a biological reality underlies their experience can be a motivational force in itself.

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atherosclerotic lesions Atlanta alcohol rehab Atlanta drug abuse rehab centers Atlanta Drug Rehab Atlanta Drug Rehab Center attack Avengers back on track back to school backup bad habbits baking banana george Banana Power bariatric surgery Barrett's Esophagus Baton Rouge battle depression bayer bayer breeze2 Bayer Contour USB bb gun BBB BE beating depression beauty become motivated before i die behealthy24.com Being sick totally sucks beta cells big blue test big foot Biomedtrics biosensor bipolar Bipolar bipolar disorder Birdman Birdman or The Unexpected Virtue of Ignorance birth birth defects birthday bladder cancer blog blogging blood glucose blood glucose levels blood pressure blood sample blood sugar blood sugar level blood sugar levels blood sugar monitor blood sugars blue shield Bluetooth bmi Body By Vi 90 Day Challenge body mass index bogo bogo. buy one get one free books bottom belly bracelet Brain Discovery Could Help Schizophrenics Breaking News breast breast feed breast 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indexes godaddy google gout grain foods green tea group guest blog guest post hair loss handicap accessible vans handicap minivans handicap vans handicapped vans happy Happy Birthday Hello Cupcake It's Me happy birthday to me :) happy holidays Harvey Birdman hba1c health health benefits health care healthier fast food healthy healthy foods healthy lifestyle healthy snack hearing loss heart heart attack heart broken Heart Disease; Cholesterol; Stroke Prevention; Diseases and Conditions; Chronic Illness; Heart Disease; Cholesterol; Stroke Prevention; Diseases and Conditions; Chronic Illness; diabetes Heart Disease; Cholesterol; Stroke Prevention; Diseases and Conditions; Chronic Illness; stroke Heart Disease; Cholesterol; Stroke Prevention; Diseases and Conditions; Chronic Illness; Vioxx heart monitor heart on my sleeve heart problems heart rate heath and beauty hello hellocupcakeitsme.com help hemoglobin Her high blood sugar high school High-Fat Foods May Be A Factor In Glucose Control hiv hiv1 hiv2 hobbytron.com holiday holiday's home security alarms home testing Homeless Homeless Shelter Homer Simpson honda hospitalization Household Income Affects Chronic Disease Control In Kids Humalog Human IPSC Humor Humulin R U-500 hunger hungry hurt on the job hyperglycima hyperglycimic hypertension hypoglycemia hypoglycemic hypoglycemic episode iBGStar Blood Glucose Monitoring System Ice Cream Image improvement including mufa foods infection infested infographic information injury inspriation insulated bag Insulin insulin injections insulin patch insulin pump insulin shot record insurance claims internal medicine Interspecies Transplant investments ios ios 5 iphone iphone 4 its iTunes Iwerkz Foldable Bluetooth Keyboard Review Jenna Mables jewelry joann joann fabric and craft store joint pain Journal of Alzheimer's Disease juwait Keek kenguru ketoacidosis occurs kicking the habbit kid kidcare kids Killings kindle kindle fire kitchen counter kombucha Labor and Industry Lamp;I lantus Late-Life Depression lawyer learning issues legal help Lexapro LG Rumor libido life lifestyle changes light box lincoln Link Between Creativity and Mental Illness Confirmed in Large-Scale Swedish Study Lipohypertrophy living loan Lone Star College Shooting loneliness lose weight losing weight loss plan lost low blood sugar low glucose levels Low income cell phone low income glasses low t low testosterone lower glucose lowering lowering glucose levels Luminaze lung health lyrics lyrics of depression Mainframe Support makeup managing diabetes Manic marijuana market mary lambert Master Card maya angelou Maya Angelou dead at 86 me meal plan meal prepping meals require medflash media / television medicaid Medical medical condition medical help Medical Review Medical Studies medical studies. medicare medicare part d medication medicines meditation melody road memory loss men's health Mental Health mental health issues Menu menu options merry christmas metabolic syndrome metabolism metabolites metersync blue miami Michael Keaton microstimulator military minimum purchases mission d.a.d mission dad Mixed Results On Computer-based Support For Diabetes mobility money money saving moods motivation mourning movie review Movie Reviews music music thearpy musings/thoughts/ideas must have MV-1 n-3 Fatty Acids Nanoparticle Suspension and Ultrasound Deliver Insulin Without Regular Injections natural home remdies natural suppliments need needing help needles needy negative thoughts neil diamond Network/Community networking new app new baby New Jersey's Universtiy of Medicine and Dentistry new medication New smart contact lens could monitor glucose for diabetics Nick Jonas night lights nissan no insulin Nook Tablet BNTV400 Review north aferica nova nordisk Now that the holidays are over obama obama phone obama wins 2012 obese Obesity obituries OCD ODD Oil Pulling Olycap omega-3 onetouch online magazines online medical records optical zoom optical123.com Optimus ERM optogenetics oral health oral hiv test oral swab oraquick overcome depression Oxygen paid marketing pancreas parental depression parkinsons party passing Paula Deen pay attention payday payday advance paying kids to attend school pedometer personal food chart Personal Post pest pests photography pills ping plam beach county Plays poet port townsend positive thoughts Postpartum Depression pot prayer pre-owned pre-school pregnancies pregnancy prepper prepping preschool prescription president prevent complications prices processed foods product Product Review products Progress Project 1811 project rudolph proline promo codes promotional Promotions psoriasis Psy public health publich education purchas questioning quit smoking raisins reaching out real butter real-estate really scare rearrange recipes Record red meat red wine reefer reflux regenerate regular exercise rehab remodel research resistance resource resources retail therapy retinopathy revamp review Reviewing the Vapourlites Blueberry/Strawberry E Juice revitalift rich foods risk roller coaster russia rx s.a.d sadness safe sex safelink Safelink wireless sale salt Sandy Hooks Elementary School Schooting saving money savings scar school School Shooting schooling scrubs for cheap seasonal affective disorder Seattle self diagnosis self help self love self medicating senior resources seo sesame seed oil sex Shindigz Coupon Code Shootings shopping Short story shot record sick side-effects simple tips SIN TAX Site Review skin care skin tags skip meals skipping meals sleep sleep apnea smaller meals smart car smart cars smart phone smoker smokes smoking social media social security sodium software sore throat sores south beach south beach diet spiral notebook sponsored sponsored review sponsored; lawyer; family; legal; issues; sponsored/guest post spot removal. ssi Statin Labels stem cell stock pile stomach pain stoner stop smoking store stress stretch marks study submit submitted substitutions successfully lose weight sugar free sugar levels sugary foods suicidal thoughts suicide Supplementation Of Alternative Fuels Could Protect The Brain During Hypoglycemia support surgery survival systemic inflammation taboo tai chi take out tax tea tech teen teen mental health teens television temporary mood test animals test strips testicle testicular cancer testing testing supplies testosterone thanksgiving the learning company the lines project. #thelinesproject thearpy therapy thought Three Devastating Statistics of Diabetes Medical Malpractice title to write love on her arm tone Tosh.O toxins Tracfone trained professional transaction travel treatment trend diets tribute to my father triglycerides tsa tweets twitter twloha type 3 diabetes type-1 type-2 type-2 diabetes U.S. Medicare Part D Can't Explain North-South Disparities UK News ultra long acting UMDNJ underlying reasons Undiagnosed Pre-Diabetes Highly Prevalent in Early Alzheimer's Disease Study unhealthy unhealthy foods up and coming artist up 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