The main question:
How is the topographical information in the
olfactory bulb transmitted to and interpreted in
the brain to decode the odor map?
Zone-to-Zone Projection
(receptor identity)
Zone-to-Zone Projection
(zone specific markers + olfactory
receptor subtypes)
coronal slice
Class I receptor
(O-MAC)
Class II receptor
(OCAM)
Markers:
O-MAC- olfactory specific medium-chain acyl-CoA synthetase
(expressed only in the D-zone).
OCAM (NCAM2) - olfactory cell adhesion molecule
(expressed only in the V-zone).
Synaptotagmin
GFP
OCAM
Two strains of mice
(specific expression of diphtera toxin)
ΔD
ΔII
wt
Receptor expression
ΔD mice
Synaptotagmin
GFP
OCAM
ΔD
Morphological consequences of ΔD (1)
(Arrangement of glomeruli in the olfactory bulb)
Appropriate glomeruli are missing in ΔD mice (“empty” spaces left – competition?)
Morphological consequences of ΔD (2)
(otherwise normal cytoarchitecture with distinct layers)
- Appropriate layers were formed (except for missing
glomeruli)
- Mitral cells in the D domain do not form dendritic
terminal tufts (probably no input from OSNs).
TH+ = PGNs
GABA+ = GCs
Synaptotagmin = synapses
Reelin+ = MCs
Functional consequences of ΔD
(Zif268 + ISI)
Dorsal surface of the OB (ISI):
- No ISI odor response in the dorsal
surface of the OB.
“unrolled” whole OB (Zif268):
- Odorants which evoke a response in
the V and D domains only activate
the V domain in ΔD mice.
ISI= intrinsic signal imaging
Zif268= immediate early gene
Behavioral consequences of ΔD (1)
(odor detection)
Pentanal - spoiled food (avoidance response)
2MB acid - spoiled food (avoidance response)
TMT - fox urine (fear avoidance response)
Habituation-dishabituation test:
- The detection thresholds for pentanal and
TMT were not affected, whereas it was tentimes higher for 2MB acid.
- In rats, the most responsive glomerulus for
pentanal is located in the V-domain. The
same seems to be true in mice, for pentanal
and for TMT.
Thus, ΔD mice can detect odors fairly normally
Behavioral consequences of ΔD (2)
(odor discrimination)
- In the odor discrimination test, hungry
mice associate 1 odorant with sugar thus
and dig longer when smelling it.
- Both wt and ΔD have similar
discrimination capabilities.
-Wt mice cannot be trained to associate
TMT with sugar (fear avoidance).
- ΔD do not have this problem (but they
do detect it).
Thus, ΔD can discriminate between odors normally
Behavioral consequences of ΔD (3)
(Innate avoidance)
- Innate preference test: in
contrast to wt mice, ΔD mice do
not display innate avoidance.
They are even attracted in some
cases.
Aversive odors
- Innate avoidance test: in
contrast to wt mice, ΔD mice do
not display innate avoidance. They
are even attracted in some cases.
The same is seen in increasing
concentrations of 2MB acid.
Thus, the D domain is necessary for innate avoidance
So… ΔD mice can detect and
discriminate between odors,
but they do not exhibit innate
avoidance.
Can they be trained?
Behavioral consequences of ΔD (3)
(Learned avoidance)
- Conditioned avoidance (preference test):
ΔD mice can be conditioned to avoid aversive odors
(LiCl-induced nausea).
Thus, the ΔD mice do not exhibit innate avoidance BUT they do
exhibit learned avoidance
The D domain is necessary for
innate avoidance, but is it
sufficient ?
ΔII mice
ΔII mice
(Do not have any glomeruli except the DI glomeruli)
Behavioral consequences of ΔII (1)
(Innate avoidance)
- Innate avoidance test: in contrast
to ΔD mice, ΔII mice do display innate
avoidance just like wt mice (except in
response to TMT).
(DII but not DI responds to
TMT so it is not avoided)
Thus, the D domain is necessary and sufficient for innate avoidance
Two different “fear pathways”:
nature and nurture
- In wt mice, the BST was strongly
activated in the BST-MA, and moderately
in the BST-LD.
- This is consistent with the previous
observation that TMT activates the BSTMA, leading to the stimulation of the HPA
axis (the “stress pathway”) in rats.
- In contrast, the BST-MA was not
activated by TMT in the ΔD mice, although
the BST-LD was activated as in wild-type
mice.
- 2MB acid response was similar between
wt and ΔD mice.
BST
Two different “fear pathways”:
nature and nurture
“The Stress Pathway”:
- TMT strongly activated the HPA axis (measured
by ACTH) in wt mice but not in ΔD mice.
- 2MB acid also moderately activated the HPA axis.
Two different “fear pathways”:
nature and nurture
The proposed model:
- TMT activates two different neuronal pathways: one for the innate fear response
(in the D-domain) and the other for the learned fear response (in the V-domain).
- For TMT, the D-domain glomeruli activate the olfactory cortex, and subsequently
the BST-MA, which activates the HPA axis and causes an increase the plasma ACTH
concentration.
“Guidelines” for discovering what a neural circuit “does”:
Eliminate a specific population of neurons
Detect morphological consequences
Detect functional consequences
Detect behavioral consequences
and to be even more persuasive, establish
sufficiency (in addition to necessity):
Eliminate all but the specific population of neurons
Show opposite behavioral consequences
Question?