BARGMANN, Cori, Chemical Regulation of Feeding/ Mating C elegans, Apr 2 2013

this is the McCormick Memorial Lecture;
4:15PM  in Berg Hall in LKS at Stanford Med School;
this is Cornelia Bargmann, PhD  (Rockefeller Univ, and HHMI)

PhD from MIT

at  UCSF  til 2004;
member of NAS;  APS;
many , many awards; (Kavli in 2012)

just won the Breakthru Prize 2013  (Mark Zuckerberg and friends);
every recipient gets 3M  bucks  (undivided);

introduced by Suzanne Pfeffer;  (Bill Newsome went across country);
big news today was that Bill and Cori will be  leading  BRAIN Project...
(formerly BAM = brain activity map project; presented in
Pres. Obama's 2013 State of the Union);
proposed budget 100M dollars for 2014  (projected 10 year project)

******************  Her talk begins****************

How is animal behavior regulated?

she looks at classic work by Tinbergen, Frisch, Lorenz...
ethologists... eg

courtship behavior: stickback fish:  Tinbergen

ducklings following their moter (imprinting)

male deer bucks duking it out for females;

bees dancing;

innate  behavior... which suggests there is a genetic template...

so how does that work...?

clearest example (in humans) is  oxytocin and vasopressin  neuropeptides
regulate  mammalian reproductive behavior...

oxytocin... helps to induce labor, lactation, mother child bonding,
milk let down response,
social recognition, pair-bonding

related molecule:  vaopressin:   aggression, mating, pair-bonding

oxytocin:  is a "one stop shopping " regulator for   mammalian  maternal behavior...

her Grad Student:  Evan Macosko; and  Jennifer  Garrison worked on this in C elegans

big surprise!  C elegans  ALSO HAS an oxytocin-like peptide with 2 conserved functional receptors
this is a 9  amino acid  peptide... clearly homologous

she shows evolution of this peptide

similar to V1br in humans

in worms it is has been labeled:
Nematocin:  and its receptors are global regulators of mating...

work done by Jennifer  Garrison:

a whole set of motor actions assoc with transfer of sperm:
(are set in motion by Nematocin)

response to contact; backing, turning, vulva search,  sperm transfer:

Nematocin is NOT REQUIRED for these behaviors but they are  much more efficient in its presence:

every part of this behavior  (in a "speed dating"  assay) was much more efficient

but let's take a step back now...

there can be  molecules in CNS that are conserved across hugely different species:
mice and nematodes...

eg oxytocin and vasopressin...

or eg  hox genes...

how do they work to regul behaviors...
this is the real subject of my talk today...

human brain:  billions of neurons and trillions of connex...
25K genes  100 known neuropeptide genes..

she pronounces C elegans  SEE Noh  rhab DITE is

302  neurons in hermaph and 389 in males.
20K genes  and abt 100 known neuropeptides in worms...

she shows wiring diagram of neurons in C elegans...
(that use  classic  neuroxmtrs:  ACh, gaba, glutamate)

but there are also NEUROMODULATORY circuits  (other than classical  neurotransmitters = xmtrs.

but they have impt role in sleep, hunger, pain, bonding, mood, addiction (in vertebrates)

so,with these modulators, how do they work,   what are their distances of action,
 timescales, how do they interact with fast synaptic circuits...

(there are also gap junctions)

look at v first paper in behavior genetics in drosophila... knopa and benzer in 1971  studying circadian rhythms...
PNAS  USA 68 (1971)

they compared  controls to mutant flies;  compared circadian rhythms  (in mutant flies... inactive state was less organized)
also see this in mice...

C elegans has distinct roaming and dwelling behaviors related to food

ROAM:  high speed with few turns (fast, straight shot)

DWELL  low speed with many turns (grazing around a confined area(

she shows a worm movie...

you see  DWELL behavior with lots of turns in a small area  and then suddenly (at 100X speed)
shoots off to another part of foraging domain...

(computer glitch: I lost 5 mins or so of notes)

she is explaining  difference btwn ROAMING states and DWELL states in C elegans...

serotonin is expressed in exactly 11 neurons in C elegans...

she cites workers who developed an HMM  hidden markov model of  this behavior

"happy"  worms DWELL (they" like the food and are content")
  when food is low quality or sparse
they shoot off to another region of habitat (ROAM)
avg dwell tau = (missed it)  abt 500 secs;
avg roam is about seconds...

Steve Flavell (in her lab) showed
that  serotonin from 2 neurons  NSM and HSN  are requried to generate this behavior...
(every single neuron in C elegans has a distinct name)

mod-1 expression in 3 neurons (ASI  AIY and RIF)
contributes to normal roaming and dwelling...

so we see the beginning of a circuit: the serotonin roaming/dwelling circuit...

3 neurons that make it and 3 neurons that  respond to it

but this circuit is orthogonal to the normal wiring diagram

is serotonin permissive or instructive?

they use  imaging calcium in foraging worms...

started with one neuron  NSM and looked at  calcium in NSM using imaging...

Steve Flavell  lined up all behaviors where calcium went up and found that  worm slows down
(during calcium release)

he also aligned  roaming evens in worms and found that serotonin PRECEDED this

(this is defective in mutants  (ie in worms with mutant  seroton release or sero receptors)

next did optogenetic methods of activation of serotonin neurons or inhibition of MOD1 neurons  and found that
it induced DWELLING...

so,  when u turn on the fiberoptic light, the animals  go from ROAMING to DWELLING
(ie  Mod1 ARch strongly stims dwelling)

this is her favorite result...

does triggering sertonin trigger dwelling?
It is involved in BOTH dwelling and roaming...

1 minute of light  keeps animals in a dwelling state (adds 6 minutes)

Serotonin induces and preserves dwelling states...

so,  what triggers this behavior (we do not know);

food supply and quality of food are impt determinants  (pharyngeal neurons)
olfactory, gustatory, and thermal clues...

**************************  new story.... a second modulator.**************

molecule here is called PDF pigment dispersing factor...

characterizedt by Paul Taghert in Cell in 1999

drosophila...

flies lacking  PDF  are randomly active during day and night (lack of PDF leads to disorganized circadian behavior)

worms with mutated PDF peptide have prolonged dwelling and shorter roaming states

these guys only have 1 minute roaming state  (before the worms had 2 sep roaming states)

steve did Cre/Lox study...

Navin Pokala  did optogentic light activated adenyl cyclase ...
(does not open ion channel... rather, activates  cAMP)
using BlaC  bacterial light -activated adenyl cyclase...

******
finally, how do these TWO SYSTEMS relate to one another
serotonin/ mod-1  and PDF/pdfr-1

animals lacking these  still can do both behaviors

in double mutants  both states are v short  (similar to cataplexy generated by lack of hypocretin: similar to work at Stfd)

so these are not required but instead just EXTEND those states.

summary:
she has shown  TWO wireless, distrib circuits for foraging bahvior.  each extends one behavioral state

role  of modulators and role of  (wired) connections is distinct;
eg  PDF is  from multiple sources  (eg from  neuron AVB)

big circuit diagram...

she shows
overlapping wiring diagrams
1)  chemical synapses  =>  locomotor patterns  (what she is calling the "wired" circuits)
and 2)  serotonin and PDF circuits  (orthogonal)  she encloses those neurons sensitive to them
in circles.

CONCLUDE:

1) multiple neurons make modulators and receptors
each neurons has other, independent function

2)  neuromod signaling is instructive  (they anticipate the behaviors) with time scales on the order of minutes
(as opposed to ms  time scales with wired connex)

they induce and stabilize pre-existing behavioral states..
perhaps converting electrical time (ms) into biochemical time...(minutes)

slide with her grad students:  abt 20 in her lab;

Q  dr fuller:  how do u get specificity with these modulators  (is it anaotmic or chemical:  how far do they travel)
A  many  factors may be involved:  molecules in the worm only need to travel abt 100 microns...

A  every neuron has several difft time scales:

Chat afterward: Cori recruited abt a month ago to head BAM/BRAIN with Bill Newsome:
wanted people independent of the original Kavli proposers. (see private notes)

Chat with Michael Lin, Stephen Smith, Jay McC, Vinod M.