PSYC 310 Lecture Notes - Lecture 8: Clozapine, Hindbrain, Proopiomelanocortin
7 May 2018
School
Department
Course
Professor
PSYC 318
Behavioural Neuroscience II
February 14th, 2018
Lecture 11/24: Neural Circuits Underlying Hunger (2)
• Last paper:
o Deciphering neuronal circuit that mediates appetite
▪ Looking at specific cell type: AgRP neurons (release peptide AgRP)
• In arcuate nucleus of hypothalamus
▪ When we stimulate these neurons, animals eat
▪ Inhibit animals don’t eat
• If you lesion AgRP neurons animals starve to death
▪ Activity is regulated by circulating leptin levels, generally correlating with
amount of fat in body
• High leptin levels low AgRP neuronal activity (body has enough fat)
• Low leptin levels high AgRP neuronal activity (body needs more fat)
o Why do mice stop eating & starve when we lesion AgRP neurons in adulthood?
▪ AgRP neurons in arcuate nucleus of hypothalamus
• Lesion these cells starvation
• These neurons are generally inhibitory, release GABA, project to 20+
places
• If you lesion these cells all the downstream targets could fire more, one
could be the reason animals aren’t eating
▪ Began by infusing GABA agonist in each region separately, the PBN in
hindbrain does save animal from starving
• Can you get animals to not die from giving anti-nausea medication?
• There is a relationship with nausea and serotonin signaling, but what is
that relationship?
o Putting anti-nausea into specific brain regions: it saved the
animals when it was put into NTS
o Created hypothetical circuit with this data
o Summary of paper
▪ Serotonin input to NTS promotes sense of nausea, increases PBN activity, in a
healthy animal kept in check by AgRP acitivty inhibiting the feeling of nausea
• Inhibiting AgRP neurons, nausea takes over and animals don’t eat
• What are the serotonin inputs to the NTS?
o RMg and Rob
▪ If you remove serotonin from them or block receptor
animals wont starve following AgRP lesion
▪ You could remove glutamate
▪ Or remove glutamate from PBN neurons
▪ These manipulations all prevent starvation from AgRP
lesions
find more resources at oneclass.com
find more resources at oneclass.com
▪ A lot of inputs to the NTS come from periphery, are sensitive to signaling
molecules like CCK (satiety signals)
• Evidence that satiety/reasons not to eat would be involved with this
circuitry
▪ Body set point: balance between nausea, hungry, for a healthy lifestyle
• Circuitry is probably always adapting/changing
• When you lesion AgRP neurons animals starve to death, but you only
need to keep them alive for 10 days but after that they can survive on
their own
• Meaning that somewhere in the circuit they realize something is wrong,
off-balance, makes an adjustment and allows animal to eat/survive
o We don’t know where these adjustments naturally take place
o Maybe there are adjustments to serotonin inputs changing nausea
signal/reducing intensity to reinstate a healthy balance
▪ Every experiment in paper began by lesioning AgRP neurons, animal starved
• What if in a healthy animal with no manipulation I removed nausea
component?
• By taking out glutamate in the PBN
o Theoretically you’d be taking out nausea component
• Using conditional glutamate knock-out mice, targeting glutamate
expression to PBN cell bodies
o Cre to PBN
o Over 3 weeks animals ate more food and gained more weight but
at a slow pace
o Became 20% heavier over three weeks
o Fairly mild, consistent with idea that the circuitry promotes a
sense of nausea and in healthy animals it is probably usually
experienced at the end of a meal indicating to us that we are full
▪ So these animals without the circuitry eat a bit more
▪ Nausea is not a reason we overeat like crazy, but it is perhaps a reason why we
eat certain smaller portions
• How does our body regulate food intake?
o Why have people gotten so much heavier now than they were 50-60 years ago?
▪ Some say it has to do with us eating more food
▪ Or lifestyle and exercise changes
▪ There are many potential answers
o Do we eat more food? This seems to be a role in societal weight gain
▪ If we study food intake: some ask what regulates the amount we eat
• Hunger and appetite
o Our food intake changes for many reasons
o If we study what regulates hunger & appetite we will get insights
into how this circuitry works, giving us targets to develop
pharmacological interventions aimed at appetite control
find more resources at oneclass.com
find more resources at oneclass.com
o Even if appetite isn’t the cause of the problem it could be the
cure
• Appetite:
o A variable influencing food intake
o Signaling molecules in blood help regulate appetite
o Fat signals decrease hunger
▪ Leptin is one of these adiposity-related signals that send feedback signals
• Adjusting systems sensitivity to all other signals
▪ Insulin is difficult to categorize, but it is released in direct proportion to blood
glucose level
• Reflects available nutrients
• Functions as a short-term satiety signal: at this given moment there’s
enough blood glucose, which should decrease hunger
• But the presence of insulin is what creates fat cells (storing of glucose
into fat cells)
o Leptin
▪ People that are deficient in leptin signaling (due to gene mutation, receptor
mutation, etc.) become extremely overweight
▪ So where is leptin acting?
• There are leptin receptors all over the brain
• Arcuate nucleus in hypothalamus
o When we remove leptin receptors form this area it tends to cause
a mild obesity phenomenon
• Removing leptin receptors from whole animal severe obesity
▪ Cell types in the arcuate nucleus:
• POMC neurons
• AgRP neurons
o Dramatic effect when we change activity of AgRP neurons
o If you lesion them animals starve to death. Why?
o AgRP neurons project to many different places, one is the PBN
o PBN
▪ Seems to convey nausea
▪ Kept in check by AgRP nausea
▪ Glutamate in PBN conveys nausea, influencing food intake, and is kept in
check by AgRP neurons in arcuate nucleus in hypothalamus
• Today’s paper: Deconstruction of a Neural Circuit for Hunger
o Research question: why do animals eat so much food the instant AgRP neurons are
activated?
o Recall paper #11 research question answer: AgRP neurons keep PBN activity in check,
which is necessary to not feel nauseous
o In paper 12 (today)
▪ Stimulate AgRP neurons, see where they project, which area causes the intense
feeding animals display as soon as they are activated?
• How do we explain causal relationships of things? Necessity vs. Sufficiency
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Lecture 11/24: neural circuits underlying hunger (2: last paper, deciphering neuronal circuit that mediates appetite, looking at specific cell type: agrp neurons (release peptide agrp) In arcuate nucleus of hypothalamus: when we stimulate these neurons, animals eat. Inhibiting agrp neurons, nausea takes over and animals don"t eat: what are the serotonin inputs to the nts, rmg and rob. This seems to be a role in societal weight gain. If we study food intake: some ask what regulates the amount we eat: hunger and appetite, our food intake changes for many reasons. If you lesion them animals starve to death. If an animal is dreaming and you stop gaba neurons from firing they immediately start acting out their dreams: how to correctly map a circuit, step one: determine where the neurons of interest make functional synaptic connections. It looks like agrp neurons project to certain brain regions.
