J Neurophysiol 100: 2–7, 2008.
First published May 7, 2008; doi:10.1152/jn.90479.2008.
Invited Review
Neurobiology of a Simple Memory
Donald A. Wilson1 and Christiane Linster2
1
Neurobehavioral Institute, Department of Zoology, University of Oklahoma, Norman, Oklahoma; and 2Department of Neurobiology
and Behavior, Cornell University, Ithaca, New York
Submitted 17 April 2008; accepted in final form 2 May 2008
INTRODUCTION
Habituation is one of the simplest forms of memory, yet
a clear understanding of its neurobiological mechanisms
remains elusive. Significant strides have been made in
invertebrates, where habituation of sensorimotor reflexes
seems to be mediated by synaptic depression (Castellucci et
al. 1970; Kandel 2001), whereas the specific mechanisms of
the depression may vary depending on the nature of induction and duration of the resulting memory (Bailey and Chen
1988; Ezzeddine and Glanzman 2003). In vertebrates, habituation of spinal cord mono-synaptic reflexes may also be
mediated by synaptic depression of sensory input (Farel and
Thompson 1976), although precise mechanisms of the synaptic plasticity are unknown.
Recent work in mammalian olfaction has proven very fruitful in the search for mechanisms of simple habituation memory. The olfactory system is a relatively simple system, highly
conserved across vertebrate evolution (Hildebrand and Shepherd 1997) and has long been implicated as having unique ties
to memorial processes. Importantly, odors evoke both autonomic reflexes and behavioral investigation, two behaviors that
can be easily quantified to allow correlation between neural
mechanism and behavioral outcome.
This review summarizes work over the past 10 yr in our
and others’ laboratories investigating the neurobiology of
olfactory habituation. Although much remains to be learned,
this work is the most complete description of the mechaAddress for reprint requests and other correspondence: D. Wilson, Dept.
of Zoology, University of Oklahoma, Norman, OK 73019 (E-mail: dwilson
@nki.rfmh.org).
2
nisms of a simple form of memory in the mammalian brain
to date, describing both necessary and sufficient central
mechanisms of behavioral response decrement with repeated stimulation.
Although habituation is classically considered a simple form
of memory, it may serve as an important building block in
more complex forms of cognition and attention (Fabiani et al.
2006; Miller et al. 1977; Postle 2005). Furthermore, disruptions in habituation and sensory gating are linked to disorders
such as schizophrenia (Ludewig et al. 2003) and autism
(Frankland et al. 2004; Ornitz et al. 1993), as well as aging
(Fabiani et al. 2006; O’Connor et al. 2008) and substance abuse
(Hunt and Morasch 2004). Thus understanding the mechanisms of this form of memory could have far reaching implications.
BEHAVIORAL PARADIGMS
Odor stimuli can elicit a variety of responses, ranging
from autonomic reflexes to behavioral arousal and investigation. Two primary behavioral paradigms have been used
to study odor habituation in mammals (Fig. 1). The simplest,
both in terms of underlying neural circuitry and interpretation is the odor-evoked heart-rate orienting reflex (Sokolov
and Vinogradova 1975). Novel sensory stimuli evoke a
bradycardia reflex, which habituates with repeated stimulation (McDonald et al. 1964). Odors activate olfactory sensory neurons within the nose, which form glutamatergic
synapses on second-order neurons called mitral cells. Mitral
cells project to the olfactory cortex, a major subdivision of
which is called the piriform cortex. Mitral cells are glutamatergic and target pyramidal cells within piriform cortex
that express N-methyl-D-aspartate (NMDA) and non-NMDA receptors, including metabotropic glutamate receptors (Shipley and
Ennis 1996). Presynaptic terminals of mitral cell axons also
express metabotropic glutamate receptors (Wada et al. 1998).
Piriform cortical pyramidal neurons project to the basolateral
amygdala, which in turn projects to the central amygdala. The
central amygdala is a major amygdaloid output nucleus, with
projections to hypothalamus and brain stem. Its projection to
the brain stem dorsal motor nucleus of the vagus leads to a
parasympathetic input to the cardiac pacemaker cells. Thus
novel odor stimulation can produce a polysynaptic heart-rate
deceleration reflex.
The second major behavioral paradigm for investigating
odor habituation in mammals is monitoring investigation of
scented objects (Cleland et al. 2002; Hunter and Murray
1989). An object scented with a novel odor is presented, and
the duration of investigation is monitored and compared
with investigation time on subsequent presentations of the
same scent. Over repeated trials, investigation decreases.
0022-3077/08 $8.00 Copyright © 2008 The American Physiological Society
www.jn.org
Downloaded from http://jn.physiology.org/ by 10.220.33.2 on June 15, 2017
Wilson DA, Linster C. Neurobiology of a simple memory. J
Neurophysiol 100: 2–7, 2008. First published May 7, 2008;
doi:10.1152/jn.90479.2008. Habituation is one of the simplest forms
of memory, yet its neurobiological mechanisms remain largely unknown in mammalian systems. This review summarizes recent multidisciplinary analyses of the neurobiology of mammalian odor
habituation including in vitro and in vivo synaptic physiology,
sensory physiology, behavioral pharmacology, and computational
modeling approaches. The findings show that a metabotropic
glutamate receptor–mediated depression of afferent synapses to the
olfactory cortex is necessary and perhaps sufficient to account for
cortical sensory adaptation and short-term behavioral habituation.
Furthermore, long-term habituation is an N-methyl-D-aspartate
(NMDA) receptor– dependent process within the olfactory bulb.
Thus there is both a pharmacological and anatomical distinction
between short-term and long-term memory for habituation. The
differential locus of change underlying short- and long-term memory leads to predictable differences in their behavioral characteristics, such as specificity.
Invited Review
NEUROBIOLOGY OF A SIMPLE MEMORY
3
There can be multiple motivating factors contributing to, or
limiting, scented object investigation, and the circuitry from
nose to motor output in this case is phenomenally complex.
Nonetheless, important insights into mechanisms of habituation have been obtained with this paradigm, and mechanisms identified in the reflex paradigm have been crossvalidated in the investigation paradigm.
Both odor-evoked heart-rate orienting reflexes and odor
investigation habituate with repeated stimulus presentations
and spontaneously recover. Habituation in both paradigms is
odor specific. Although not investigated in the heart-rate reflex
paradigm, habituation of odor investigation can show both
short- and long-term forms, with important behavioral and
neurobiological differences as described below. When combined with electrophysiological and pharmacological techniques, these two behavioral assays have provided excellent
insight into the mechanisms of odor habituation.
J Neurophysiol • VOL
OLFACTORY SENSORY NEURON ADAPTATION
Although olfactory sensory neurons can adapt to repeated or
prolonged odor stimulation (Kurahashi and Menini 1997;
Zufall and Leinders-Zufall 2000), behavioral odor habituation
is a central phenomenon. As is the case in other sensory
systems, central olfactory neurons show greater response decrement than peripheral receptors, with piriform cortical neurons showing rapid, nearly complete response adaptation
within seconds or minutes of stimulation in both rodents
(Wilson 1998a) and humans (Sobel et al. 2000). In a direct
comparison of receptor adaptation and perceptual habituation
in humans, Hummel et al. (1996) showed that changes in the
periphery could not account for the magnitude of decrease in
perceptual intensity estimates. Disruption of sensory neuron adaptation in transgenic mice can impair odor perception (Kelliher
et al. 2003); however, as described below, these effects are most
100 • JULY 2008 •
www.jn.org
Downloaded from http://jn.physiology.org/ by 10.220.33.2 on June 15, 2017
FIG. 1. Experimental paradigms. A: schematic representation of the electrophysiological experiments. Intra- and extracellular recordings were made from
pyramidal cells in anterior piriform cortex (PCx). Odor responsiveness of individual cells was first tested with a 2-s odor stimulus. Habituation of the odor
response was achieved by either presenting the same odorant for 50 continuous s or presenting ten 2-s odor stimuli separated by 30 s. A 2-s odor pulse tested
the posthabituation response to the same odorant. Typically, pyramidal cell responses were significantly reduced by the prolonged or intermittent stimulation.
B: bradycardia autonomic reflex habituation paradigm for adult rats. Odor-evoked heartrate orienting responses to 4-s odor stimuli were monitored with telemetry
devices (inset) before and after stimulus repetition with 10- to 30-s interstimulus intervals. These orienting responses showed pronounced habituation after 30 – 60
trials. C: behavioral habituation paradigm for adult rats and mice. Odors are presented to the mouse in their home cage, either by hanging a tea ball containing
an odor-saturated swab from the cage roof or by presenting odor-saturated filter paper on the roof of the cage. Investigation of the odorant is measured during
odor presentation. Animals are typically first presented with a blank (mineral only) stimulus, followed by 4 presentations of the habituation odor. A different test
odor is presented during the 6th trial. In the short-term paradigm, odors are presented for 20 s separated by 10-s intertrial intervals, whereas in the long-term
paradigm, odors are presented for 50 s separated by 5-min intertrial intervals.
Invited Review
4
D. A. WILSON AND C. LINSTER
likely caused by aberrant patterns of central circuit activation
rather than a direct effect on habituation per se.
CORTICAL ADAPTATION AND
SHORT-TERM HABITUATION
J Neurophysiol • VOL
LONG-TERM HABITUATION
In addition to short-term habituation described above, extended and/or spaced odor exposure can lead to long-term
habituation. In humans exposed daily to odors in the home or
workplace, habituation to the exposed odor (elevated detection
threshold) can last weeks (Dalton 2000; Dalton and Wysocki
1996). Similarly, in rodents, depending on the parameters of
habituation induction, odor habituation can last either a few
minutes following rapid, short presentations or ⬎1 h following
spaced, long presentations (McNamara et al. 2008).
In invertebrates, the behavioral characteristics and neurobiological mechanisms of short- and long-term habituation can
differ in several features, including the presence or absence of
anatomical changes and the involvement of specific receptor or
second messenger cascades (Bailey and Chen 1988; Rose et al.
2003; Stopfer et al. 1996). We have recently begun a comparison of both the behavioral characteristics and neural mechanisms of long-term habituation in the mammal with a specific
emphasis on identifying differences with short-term habituation. Our early results suggest that long-term habituation induced by spaced, prolonged odor exposure differs from shortterm habituation in the specific glutamatergic receptors involved, the locus of change within the olfactory pathway, and
in its stimulus specificity (McNamara et al. 2008).
Short, rapidly presented (10-s interstimulus interval) odor
stimuli induce a short-term habituation of odor investigation
lasting a few minutes (McNamara et al. 2008; Yadon and
Wilson 2005). As noted above, blockade of group III
metabotropic glutamate receptors, systemically (McNamara
et al. 2008) or via intrapiriform cortical infusions (Yadon
and Wilson 2005) prevents or reduces this habituation. This
short-term habituation is highly odor specific, with very little
cross-habituation even between molecularly similar odorants
(Fletcher and Wilson 2002; McNamara et al. 2008), as is
adaptation of the responses of piriform cortex single units to
odors (Wilson 2000a,b).
FIG. 2. Schematic summary of localization, mechanisms and characteristics of short- and long-term odor habituation based on results described in the
text.
100 • JULY 2008 •
www.jn.org
Downloaded from http://jn.physiology.org/ by 10.220.33.2 on June 15, 2017
Simultaneous recordings of second-order mitral cells and
their target piriform cortical pyramidal cells showed that the
cortical neurons adapt to repeated or prolonged odor stimulation more rapidly and completely than their afferent mitral cells
(Wilson 1998a). Mitral cells do adapt to odors (Gray and
Skinner 1988; Scott 1977; Wilson and Sullivan 1992); however, adaptation of their downstream targets is both faster and
more complete. The cortical adaptation is odor-specific, showing minimal cross-adaptation between molecularly similar or
dissimilar odorants and even relatively little cross-adaptation
between a familiar odor mixture and its components (Wilson
2000a,b, 2003). In vivo intracellular recordings showed that
this cortical adaptation is associated with depression of the
glutamatergic mitral-pyramidal cell synapse and that this synaptic depression recovers with the same time course as the
short-term adaptation of odor-evoked postsynaptic potentials
(Wilson 1998b).
In vitro, electrical stimulation of mitral cell axons in a
pattern mimicking mitral cell odor-evoked activity produces a
similar synaptic depression (Best and Wilson 2004; Thompson
et al. 2005). This depression is homosynaptic (Best and Wilson
2004), perhaps contributing to the odor specificity of cortical
adaptation. Additional in vitro work showed that the activitydependent cortical afferent synaptic depression was dependent
on group III metabotropic glutamate receptors (Best and Wilson 2004), which have been found presynaptically on mitral
cell axon terminals (Wada et al. 1998). Pharmacological blockade of these receptors in vitro, with either (RS)-a-cyclopropyl4-phosphonophenylglycine (CPPG) (Best and Wilson 2004) or
(RS)-a-methylserine-O-phosphate (MSOP) (M. Kadohisa and
D. A. Wilson, unpublished observations) prevents afferent
synaptic depression.
Antagonists of group III metabotropic glutamate receptors
not only prevent synaptic adaptation in vitro but also prevent or
reduce odor habituation at the behavioral level. Bilateral,
intrapiriform cortex infusions of CPPG block habituation of the
odor-evoked heart-rate orienting response (Best et al. 2005)
and reduce habituation of investigation of scented objects
(Yadon and Wilson 2005). Similarly, systemic injections of the
metabotropic glutamate receptor antagonist LY341495 reduce
short-term odor investigation habituation (McNamara et al.
2008). Intracerebral infusions distant to the piriform cortex
produced no significant effect on habituation of odor object
investigation (Yadon and Wilson 2005). Preliminary results
(Wilson, unpublished observations) further suggest that intrapiriform infusions of the metabotropic glutamate receptor agonist L-(⫹)-2-amino-4-phosphonobutyric acid produce a depression of odor-evoked heart-rate orienting reflexes, comparable to those seen during habituation.
Together, these results strongly argue that depression of
mitral cell afferents to the piriform cortex, via a presynaptic
metabotropic glutamate receptor–mediated mechanism, leads
to both short-term cortical odor adaptation and short-term
behavioral odor habituation. Metabotropic glutamate receptors
have been implicated in synaptic depression in several systems
(Bandrowski et al. 2002; Bespalov et al. 2007; Burke and
Hablitz 1994; Schoppa and Westbrook 1997; Weber et al.
2002). However, we believe the observations reported here are
the most direct link between these receptors, synaptic depression, and short-term behavioral habituation, and provide the
most complete mechanistic description of this form of simple
memory in the mammalian brain.
Invited Review
NEUROBIOLOGY OF A SIMPLE MEMORY
In contrast, habituation induced by spaced (5-min interstimulus interval) odor stimuli lasts ⱖ1 h and is unaffected by
metabotropic receptor blockade. Rather, systemic injections of
the NMDA receptor antagonist MK-801 significantly block
long-term habituation (McNamara et al. 2008). MK-801 injections have no effect on short-term habituation (McNamara
et al. 2008). Furthermore, although the piriform cortex is a
critical locus for short-term habituation, infusions of MK-801
locally into the olfactory bulb block long-term habituation
(McNamara et al. 2008). Thus McNamara et al. (2008) showed
a double-dissociation between short- and long-term habituation, with NMDA receptor antagonists blocking long-term
habituation but having no impact on short-term habituation and
metabotropic glutamate receptors blocking short-term habituation but having no effect on long-term habituation. Finally,
5
the NMDA mechanism of long-term habituation seems to be
localized within the olfactory bulb, whereas the metabotropic
glutamate receptor mechanism of short-term habituation seems
localized within the piriform cortex.
Precisely how NMDA receptor activation within the olfactory bulb leads to long-term odor habituation is unclear.
NMDA receptors are involved in a variety of functions within
olfactory bulb circuits, including response of second-order
neurons or olfactory sensory neuron input (Ennis et al. 1998),
mitral cell to mitral cell cross-talk and/or auto-excitation
(Isaacson 1999; Salin et al. 2001; Schoppa and Urban 2003),
and mitral cell interactions with inhibitory interneurons including granule cells (Isaacson and Strowbridge 1998). Furthermore, NMDA receptors are involved in olfactory bulb circuit
plasticity (Ennis et al. 1998; Mandairon et al. 2006; Tyler et al.
Downloaded from http://jn.physiology.org/ by 10.220.33.2 on June 15, 2017
FIG. 3. Computational modeling. A: the model included neural representations of olfactory sensory neurons (data not shown), olfactory bulb mitral,
periglomerular and granule cells (data not shown), and cortical pyramidal cells (pyr), feedforward (ff), and feedback (fb) local interneurons. Short-term synaptic
adaptation was implemented for the excitatory glutamatergic synapses between olfactory bulb mitral and pyramidal cells. Short-term synaptic potentiation was
implemented for intrinsic synapses between cortical pyramidal cells. Projection patterns between mitral and pyramidal cells and between pyramidal cells were
chosen randomly with relatively low (0.2) connection probability. B: odor background segmentation. The graph shows the average number of spikes per
pyramidal cell in response to a background and a control odorant before (pre-exposure) and after (postexposure) prolonged exposure to the background odorant.
Because of synaptic adaptation of synapses activated during the exposure period, the average response across pyramidal cells is significantly reduced to the
background odor but not to the control odor. This mechanism can serve for odor-background segmentation. C and D: interplay between afferent synaptic adaptation
and intrinsic synaptic potentiation. C: example pyramidal cell responses to 2 odors (A and B), modeled to be highly similar (i.e., activating 50% of the same sensory
neurons). Before exposure, pyramidal cells respond to both or either 1 of the 2 odorants (left). After exposure to odor A, during which both synaptic adaptation and
potentiation were implemented, pyramidal cell responses to odor A are strongly suppressed, whereas responses to odor B are only weakly suppressed (middle). Exposure
to odor A with potentiation not active leads to strong suppression of both odorants A and B. D: responses to a series of similar odorants modeling chemically similar
esters with differing carbon chain length. The graph shows the responses to the exposure odorant and several chemically similar odorants as percent response to the best
odor during pre-exposure. Note that the response to the exposure odorant is more selectively suppresses when both synaptic adaptation and potentiation are implemented
as compared with adaptation alone.
J Neurophysiol • VOL
100 • JULY 2008 •
www.jn.org
Invited Review
6
D. A. WILSON AND C. LINSTER
COMPUTATIONAL MODELING
The insights gained into mechanisms of habituation have led
to predictions regarding its role in cognitive and perceptual
phenomena. The most thoroughly studied to date has been an
examination of the role of habituation and cortical adaptation
in perceptual background segmentation. The relative simplicity
of the olfactory system has allowed us to examine background
segmentation with electrophysiological methods (Kadohisa
and Wilson 2006), behavioral methods, and computational
modeling (Linster et al. 2007).
Using a combined model of olfactory bulb and cortex,
Linster et al. (2007) showed how synaptic adaptation at the
olfactory bulb input to the piriform cortex can be sufficient to
create odor specific adaptation in olfactory cortex neurons and
that this feature can produce odor background segmentation
(Fig. 3). Further modeling including short-term synaptic potentiation at piriform cortex pyramidal synapses suggested that
it is the interaction between synaptic adaptation at afferent
synapses and synaptic potentiation at intrinsic synapses that
ensure the high odor selectivity observed in electrophysiological (Wilson 2000a,b, 2003) and behavioral (McNamara et al.
2008) short-term habituation.
SUMMARY
In summary, the olfactory system presents unique opportunities to examine the neurobiology of simple memory. The data
described here show both a pharmacological and anatomical
distinction between short-term and long-term memory for habituation. Furthermore, the differential locus of change underlying short- and long-term memory lead to predictable differences in their characteristics, such as specificity. These findings
suggest that habituation in the mammalian brain is a rich,
complex, and distributed process—not nearly as simple as
generally described.
ACKNOWLEDGMENTS
Present address of D. A. Wilson: Emotional Brain Institute, Nathan Kline
Institute, and the Department of Child and Adolescent Psychiatry, New York
University, New York, New York.
GRANTS
Preparation of this manuscript was funded by National Science Foundation
Grant CNS 0338981 to C. Linster and D. A. Wilson.
J Neurophysiol • VOL
REFERENCES
Bailey CH, Chen M. Morphological basis of short-term habituation in Aplysia. J Neurosci 8: 2452–2459, 1988.
Bandrowski AE, Moore SL, Ashe JH. Activation of metabotropic glutamate
receptors by repetitive stimulation in auditory cortex. Synapse 44: 146 –157,
2002.
Bespalov A, Jongen-Relo AL, van Gaalen M, Harich S, Schoemaker H,
Gross G. Habituation deficits induced by metabotropic glutamate receptors
2/3 receptor blockade in mice: reversal by antipsychotic drugs. J Pharmacol
Exp Ther 320: 944 –950, 2007.
Best AR, Thompson JV, Fletcher ML, Wilson DA. Cortical metabotropic
glutamate receptors contribute to habituation of a simple odor-evoked
behavior. J Neurosci 25: 2513–2517, 2005.
Best AR, Wilson DA. Coordinate synaptic mechanisms contributing to olfactory cortical adaptation. J Neurosci 24: 652– 660, 2004.
Buonviso N, Chaput M. Olfactory experience decreases responsiveness of the
olfactory bulb in the adult rat. Neuroscience 95: 325–332, 2000.
Buonviso N, Gervais R, Chalansonnet M, Chaput M. Short-lasting exposure
to one odour decreases general reactivity in the olfactory bulb of adult rats.
Eur J Neurosci 10: 2472–2475, 1998.
Burke JP, Hablitz JJ. Presynaptic depression of synaptic transmission mediated by activation of metabotropic glutamate receptors in rat neocortex.
J Neurosci 14: 5120 –5130, 1994.
Castellucci V, Pinsker H, Kupfermann I, Kandel ER. Neuronal mechanisms of habituation and dishabituation of the gill-withdrawal reflex in
Aplysia. Science 167: 1745–1748, 1970.
Cleland TA, Morse A, Yue EL, Linster C. Behavioral models of odor
similarity. Behav Neurosci 116: 222–231, 2002.
Dalton P. Psychophysical and behavioral characteristics of olfactory adaptation. Chem Senses 25: 487– 492, 2000.
Dalton P, Wysocki CJ. The nature and duration of adaptation following
long-term odor exposure. Percept Psychophys 58: 781–792, 1996.
Ennis M, Linster C, Aroniadou-Anderjaska V, Ciombor K, Shipley MT.
Glutamate and synaptic plasticity at mammalian primary olfactory synapses.
Ann NY Acad Sci 855: 457– 466, 1998.
Ezzeddine Y, Glanzman DL. Prolonged habituation of the gill-withdrawal
reflex in Aplysia depends on protein synthesis, protein phosphatase activity,
and postsynaptic glutamate receptors. J Neurosci 23: 9585–9594, 2003.
Fabiani M, Low KA, Wee E, Sable JJ, Gratton G. Reduced suppression or
labile memory? Mechanisms of inefficient filtering of irrelevant information
in older adults. J Cogn Neurosci 18: 637– 650, 2006.
Farel PB, Thompson RF. Habituation of a monosynaptic response in frog
spinal cord: evidence for a presynaptic mechanism. J Neurophysiol 39:
661– 666, 1976.
Fletcher ML, Wilson DA. Experience modifies olfactory acuity: acetylcholine-dependent learning decreases behavioral generalization between similar
odorants. J Neurosci 22: RC201, 2002.
Frankland PW, Wang Y, Rosner B, Shimizu T, Balleine BW, Dykens EM,
Ornitz EM, Silva AJ. Sensorimotor gating abnormalities in young males
with fragile X syndrome and Fmr1-knockout mice. Mol Psychiatry 9:
417– 425, 2004.
Gray CM, Skinner JE. Field potential response changes in the rabbit
olfactory bulb accompany behavioral habituation during the repeated presentation of unreinforced odors. Exp Brain Res 73: 189 –197, 1988.
Hildebrand JG, Shepherd GM. Mechanisms of olfactory discrimination:
converging evidence for common principles across phyla. Annu Rev Neurosci 20: 595– 631, 1997.
Hummel T, Knecht M, Kobal G. Peripherally obtained electrophysiological
responses to olfactory stimulation in man: electro-olfactograms exhibit a
smaller degree of desensitization compared with subjective intensity estimates. Brain Res 717: 160 –164, 1996.
Hunt PS, Morasch KC. Modality-specific impairments in response habituation following postnatal binge ethanol. Neurotoxicol Teratol 26: 451– 459,
2004.
Hunter AJ, Murray TK. Cholinergic mechanisms in a simple test of olfactory
learning in the rat. Psychopharmacology (Berl) 99: 270 –275, 1989.
Isaacson JS. Glutamate spillover mediates excitatory transmission in the rat
olfactory bulb. Neuron 23: 377–384, 1999.
Isaacson JS, Strowbridge BW. Olfactory reciprocal synapses: dendritic
signaling in the CNS. Neuron 20: 749 –761, 1998.
Kadohisa M, Wilson DA. Olfactory cortical adaptation facilitates detection of
odors against background. J Neurophysiol 95: 1888 –1896, 2006.
100 • JULY 2008 •
www.jn.org
Downloaded from http://jn.physiology.org/ by 10.220.33.2 on June 15, 2017
2007; Wilson 1995) and olfactory memory formation (Kendrick et al. 1992; Lincoln et al. 1988; Mandairon et al. 2006).
Further work will be required to identify the specific process of
olfactory bulb NMDA receptor involvement in long-term odor
habituation.
The different circuits underlying short- and long-term habituation (Fig. 2) may be expected to affect other characteristics
of habituation, such as its specificity. For example, olfactory
bulb mitral cells show strong cross-habituation (strong generalization: Buonviso and Chaput 2000; Buonviso et al. 1998;
Wilson 2000a), whereas piriform cortical neurons show little
cross-habituation (Wilson 2000a). In concert with these physiological differences, McNamara et al. (2008) showed behaviorally that cortically mediated short-term habituation of odor
investigation is highly odor specific, whereas olfactory bulb–
mediated long-term habituation shows much more stimulus
generalization.
Invited Review
NEUROBIOLOGY OF A SIMPLE MEMORY
J Neurophysiol • VOL
Scott JW. A measure of extracellular unit responses to repeated stimulation
applied to observations of the time course of olfactory responses. Brain Res
132: 247–258, 1977.
Shipley MT, Ennis M. Functional organization of olfactory system. J Neurobiol 30: 123–176, 1996.
Sobel N, Prabhakaran V, Zhao Z, Desmond JE, Glover GH, Sullivan EV,
Gabrieli JD. Time course of odorant-induced activation in the human
primary olfactory cortex. J Neurophysiol 83: 537–551, 2000.
Sokolov EN, Vinogradova OS. Neuronal Mechanisms of the Orienting Reflex.
Hillsdale, NJ: L. Erlbaum Associates, 1975, p. viii.
Stopfer M, Chen X, Tai YT, Huang GS, Carew TJ. Site specificity of
short-term and long-term habituation in the tail-elicited siphon withdrawal
reflex of Aplysia. J Neurosci 16: 4923– 4932, 1996.
Thompson JV, Best AR, Wilson DA. Ontogeny of cortical synaptic depression underlying olfactory sensory gating in the rat. Brain Res Dev Brain Res
158: 107–110, 2005.
Tyler WJ, Petzold GC, Pal SK, Murthy VN. Experience-dependent modification of primary sensory synapses in the mammalian olfactory bulb.
J Neurosci 27: 9427–9438, 2007.
Wada E, Shigemoto R, Kinoshita A, Ohishi H, Mizuno N. Metabotropic
glutamate receptor subtypes in axon terminals of projection fibers from the
main and accessory olfactory bulbs: a light and electron microscopic
immunohistochemical study in the rat. J Comp Neurol 393: 493–504, 1998.
Weber M, Schnitzler HU, Schmid S. Synaptic plasticity in the acoustic startle
pathway: the neuronal basis for short-term habituation? Eur J Neurosci 16:
1325–1332, 2002.
Wilson DA. NMDA receptors mediate expression of one form of functional
plasticity induced by olfactory deprivation. Brain Res 677: 238 –242, 1995.
Wilson DA. Habituation of odor responses in the rat anterior piriform cortex.
J Neurophysiol 79: 1425–1440, 1998a.
Wilson DA. Synaptic correlates of odor habituation in the rat anterior piriform
cortex. J Neurophysiol 80: 998 –1001, 1998b.
Wilson DA. Comparison of odor receptive field plasticity in the rat olfactory
bulb and anterior piriform cortex. J Neurophysiol 84: 3036 –3042, 2000a.
Wilson DA. Odor specificity of habituation in the rat anterior piriform cortex.
J Neurophysiol 83: 139 –145, 2000b.
Wilson DA. Rapid, experience-induced enhancement in odorant discrimination by anterior piriform cortex neurons. J Neurophysiol 90: 65–72, 2003.
Wilson DA, Sullivan RM. Blockade of mitral/tufted cell habituation to odors
by association with reward: a preliminary note. Brain Res 594: 143–145,
1992.
Yadon CA, Wilson DA. The role of metabotropic glutamate receptors and
cortical adaptation in habituation of odor-guided behavior. Learn Mem 12:
601– 605, 2005.
Zufall F, Leinders-Zufall T. The cellular and molecular basis of odor
adaptation. Chem Senses 25: 473– 481, 2000.
100 • JULY 2008 •
www.jn.org
Downloaded from http://jn.physiology.org/ by 10.220.33.2 on June 15, 2017
Kandel ER. The molecular biology of memory storage: a dialogue between
genes and synapses. Science 294: 1030 –1038, 2001.
Kelliher KR, Ziesmann J, Munger SD, Reed RR, Zufall F. Importance of
the CNGA4 channel gene for odor discrimination and adaptation in behaving mice. Proc Natl Acad Sci USA 100: 4299 – 4304, 2003.
Kendrick KM, Levy F, Keverne EB. Changes in the sensory processing of
olfactory signals induced by birth in sleep. Science 256: 833– 836, 1992.
Kurahashi T, Menini A. Mechanism of odorant adaptation in the olfactory
receptor cell. Nature 385: 725–729, 1997.
Lincoln J, Coopersmith R, Harris EW, Cotman CW, Leon M. NMDA
receptor activation and early olfactory learning. Brain Res 467: 309 –312, 1988.
Linster C, Henry L, Kadohisa M, Wilson DA. Synaptic adaptation and
odor-background segmentation. Neurobiol Learn Mem 87: 352–360, 2007.
Ludewig K, Geyer MA, Vollenweider FX. Deficits in prepulse inhibition and
habituation in never-medicated, first-episode schizophrenia. Biol Psychiatry
54: 121–128, 2003.
Mandairon N, Stack C, Kiselycznyk C, Linster C. Broad activation of the
olfactory bulb produces long-lasting changes in odor perception. Proc Natl
Acad Sci USA 103: 13543–13548, 2006.
McDonald DG, Johnson LC, Hord DJ. Habituation of the orienting response
in alert and drowsy subjects. Psychophysiology 57: 163–173, 1964.
McNamara AM, Magidson PD, Linster C, Wilson DA, Cleland TA.
Distinct neural mechanisms mediate olfactory memory formation at different timescales. Learn Mem 15: 117–125, 2008.
Miller DJ, Ryan EB, Short EJ, Ries PG, McGuire MD, Culler MP.
Relationship between early habituation and later cognitive performance in
infancy. Child Dev 48: 658 – 661, 1977.
O’Connor KW, Loughlin PJ, Redfern MS, Sparto PJ. Postural adaptations
to repeated optic flow stimulation in older adults. Gait Posture 2008. In
press.
Ornitz EM, Lane SJ, Sugiyama T, de Traversay J. Startle modulation
studies in autism. J Autism Dev Disord 23: 619 – 637, 1993.
Postle BR. Delay-period activity in the prefrontal cortex: one function is
sensory gating. J Cogn Neurosci 17: 1679 –1690, 2005.
Rose JK, Kaun KR, Chen SH, Rankin CH. GLR-1, a non-NMDA glutamate
receptor homolog, is critical for long-term memory in Caenorhabditis
elegans. J Neurosci 23: 9595–9599, 2003.
Salin PA, Lledo PM, Vincent JD, Charpak S. Dendritic glutamate autoreceptors modulate signal processing in rat mitral cells. J Neurophysiol 85:
1275–1282, 2001.
Schoppa NE, Urban NN. Dendritic processing within olfactory bulb circuits.
Trends Neurosci 26: 501–506, 2003.
Schoppa NE, Westbrook GL. Modulation of mEPSCs in olfactory bulb
mitral cells by metabotropic glutamate receptors. J Neurophysiol 78: 1468 –
1475, 1997.
7