Chemical Senses Vol. 30 No. suppl 1 © Oxford University
Press 2005; all rights reserved
Developmental Changes in Olfactory Behavior and Limbic Circuitry
Department of Zoology, University of Oklahoma, Norman, OK, USA
Correspondence to be sent to: Regina Sullivan, e-mail: rsullivan{at}ou.edu
Key words: amygdala, corticosterone, development, fear, fear conditioning, learning, olfactory bulb, predator odor, stress
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Introduction |
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 Top Introduction Altering the day at...Fear to predator odor...Ontogeny of fear to...AcknowledgementsReferences |
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The olfactory system of infant rats is not an immature version of the adult system but is organized to ensure infants form the attachment to the caregiver necessary for survival. We study a sensitive period during the first nine days of life when rat pups have unique learning abilities that ensure pups quickly and reliably learn a preference for the maternal odor that underlies pup orientation to the mother and nursing. There are two unique aspects of this early learning. First, neonatal rat pups have an increased ability to acquire odor preferences. It produces corresponding metabolic and anatomical changes in the olfactory bulb that is supported by norepinephrine from the hyperfunctioning neonatal locus coeruleus (Sullivan, 2003
;
Moriceau and Sullivan, 2004a). The
neonatal learned odor preference and the associated olfactory bulb changes are maintained
into adulthood. Secondly, which is the focus of this paper, neonatal pups have a
decreased ability to acquire learned odor aversions (Sullivan et al., 1986, 2000;
Camp and Rudy, 1988), presumably due
to lack of amygdala participation in aversive conditioning (assessed by 2-DG;
Sullivan et al., 2000).
Specifically, during the sensitive period, a novel odor paired with painful 0.5mA shock
produces a subsequent odor preference in pups. [Neonatal (<PN9) pups could learn
an odor aversion if that odor is paired with malaise (LiCl or strong shock >1.2mA;
Spear and Rudy, 1991).] It
should be noted that pups of this age feel pain (Haroutunian and Campbell, 1979;
Barr, 1995) and do not show a
preference for the shock, only the odor. We also find that the amygdala, a brain area
necessary for adult odor–shock fear conditioning (Fanselow and Gale, 2003;
Maren, 2003), does not participate in
this shock-induced odor preference (Sullivan
et al., 2000). We suggest that the failure of the amygdala to
participate in the neonatal sensitive period odor shock conditioning results in the odor
preference. On postnatal day (PN) 10, when walking emerges (Bolles and Woods, 1964), naïve pups easily learn to
avoid odors paired with shock and the amygdala participates in this conditioning
(Sullivan et al., 2000). We
suggest that the functional emergence of the amygdala in odor shock conditioning at PN10
permits pups to learn a shock-induced odor aversion using a fear conditioning paradigm.
Thus, during the sensitive period the neonate appears to use a unique neural circuitry
for learning. Considering structures that support adult learning are probably not
functional in the neonate (amygdala, hippocampus, cerebellum, frontal cortex) and
connections between these areas are still maturing, it is not surprising that neonatal
pups are using a different circuit (Verwer et
al., 1996;
Nair and Gonzalez-Lima, 1999;
Stanton, 2000; reviewed in
Sullivan, 2003). |
Altering the day at which the sensitive period ends |
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TopIntroductionAltering the day at...Fear to predator odor...Ontogeny of fear to...AcknowledgementsReferences |
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We have been able to modify the age that pups begin to learn an odor aversion from odor–shock conditioning and participation of the amygdala simply by modifying corticosterone (CORT) levels (Moriceau and Sullivan, 2004b
). The neonate’s sensitive-period is coincident with the
‘stress hyporesponsive period’ (SHP). The SHP is characterized by low basal
CORT levels and the inability of most stressful stimuli to increase CORT, such as shock
(Levine, 1962), unless pups
experience prolonged separation from the mother (Stanton et al., 1988). In our experiments, pups
are away from the mother for 
1 h, which does not alter CORT levels and is within the
range mothers would normally be absent from the nest. We assessed the effects of
manipulating CORT levels by increasing and removing CORT, respectively, during (PN8) and
after (PN12) the sensitive period. We found that CORT (3 mg/kg, i.p.) prior to
conditioning enabled PN8 PAIRED pups (sensitive period) precociously to learn an odor
aversion, prevented the acquisition of the olfactory bulb learning-induced neural changes
and permitted the amygdala (basolateral/lateral complex) to participate in the learning.
Moreover, PN12 CORT depleted (adrenalectomy, ADX) pups continued shock-induced odor
preference learning, acquired the olfactory bulb neural changes and the amygdala did not
participate in the learning. CORT replacement in ADX PN12 pups enabled pups to learn a
shock-induced odor aversion, prevented the olfactory bulb learning-induced changes and
the amygdala participated in odor–shock conditioning. We propose that it is the
activation of the amygdala by CORT, either directly or indirectly, that permits the odor
aversion learning and determines the end of the pups sensitive period for learning. |
Fear to predator odor and amygdala participation also emerges at PN10 |
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TopIntroductionAltering the day at...Fear to predator odor...Ontogeny of fear to...AcknowledgementsReferences |
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Under most circumstances, adult male rats eat pups and their odor is therefore classified as a predator odor to pups (Mennella and Moltz, 1988
). Fear to predator odors, as measured by freezing to adult
male odor, emerges at PN10 in rat pups (Takahashi
and Rubin, 1993) and is coincident with the amygdala participating in the
response to predator odor (Wiedenmayer and Barr,
2001). This suggests that the amygdala is important in pups’
responsiveness to naturally fearful odors. |
Ontogeny of fear to predator odors can be controlled by CORT |
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TopIntroductionAltering the day at...Fear to predator odor...Ontogeny of fear to...AcknowledgementsReferences |
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In striking similarity to learned fear, Takahashi and Rubin (1993
) have shown
that the emergence of fear to predator odor is strongly influenced by increases in CORT
levels associated with the end of the stress hyporesponsive period. Specifically, they
were able to precociously induce freezing in neonatal pups by injecting CORT. In strong
support of this work, prolonged exposure to predator odor (30 min) in neonatal pups can
elicit freezing (Gould and Cameron,
1997), although this duration of exposure increases endogenous CORT levels
(Moriceau and Sullivan, 2004b). In
our recent work, we replicated the behavioral work of
Takahashi and Rubin (1993) and
assessed whether amygdala activation was coincident with the behavioral manipulations
induced by CORT manipulation. Our results indicate that we could prematurely activate the
expression of freezing and the basolateral/lateral complex of the amygdala (cfos) in
neonates through exogenous CORT. Additionally, we were also able to retard the
developmental expression of fear to predator odor and amygdala activation through
adrenalectomy (ADX). These results replicate
Wiedenmayer and Barr (2001) and
Takahashi and Rubin (1993), but
extend their results to suggest CORT is implicated in amygdala (basolateral complex)
activation, either directly or indirectly, to permit the expression of infant fear. This
is in contrast to the adult literature, which suggests predator odor activates the
central nucleus, basolateral complex, and medial amygdala (Kemble et al., 1990;
Misslin, 2003;
Li et al., 2004). However,
the central and the medial nuclei of the amygdala are not activated, at least by
naturally fearful odors until after weaning (Wiedenmayer and Barr, 2001) suggesting the role of specific
amygdala nuclei may change during development depending on the task.
These results indicate that CORT has the ability to alter the ontogenetic emergence
of both learned and natural fear and suggesting the attachment system could be modified
by environmental factors. First, the sensory stimulation and milk pups receive during
maternal interactions maintains pups’ low CORT levels (Kent et al., 1997). Secondly, a stressed mother may
raise pups’ CORT level two ways: by decreasing her maternal care and transmitting
her high CORT levels to pups through her milk (Yeh, 1984).
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Acknowledgements |
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TopIntroductionAltering the day at...Fear to predator odor...Ontogeny of fear to...AcknowledgementsReferences |
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Work described here was supported by grants from NSF-IBN and NIH-NICHD.
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