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Comparative Study
. 2009 Dec 16;29(50):15745-55.
doi: 10.1523/JNEUROSCI.4106-09.2009.

Early-life stress disrupts attachment learning: the role of amygdala corticosterone, locus ceruleus corticotropin releasing hormone, and olfactory bulb norepinephrine

Stephanie Moriceau  1 , Kiseko Shionoya, Katherine Jakubs, Regina M Sullivan
Affiliations
Comparative Study

Early-life stress disrupts attachment learning: the role of amygdala corticosterone, locus ceruleus corticotropin releasing hormone, and olfactory bulb norepinephrine

Stephanie Moriceau et al. J Neurosci. .

Abstract

Infant rats require maternal odor learning to guide pups' proximity-seeking of the mother and nursing. Maternal odor learning occurs using a simple learning circuit including robust olfactory bulb norepinephrine (NE), release from the locus ceruleus (LC), and amygdala suppression by low corticosterone (CORT). Early-life stress increases NE but also CORT, and we questioned whether early-life stress disrupted attachment learning and its neural correlates [2-deoxyglucose (2-DG) autoradiography]. Neonatal rats were normally reared or stressed-reared during the first 6 d of life by providing the mother with insufficient bedding for nest building and were odor-0.5 mA shock conditioned at 7 d old. Normally reared paired pups exhibited typical odor approach learning and associated olfactory bulb enhanced 2-DG uptake. However, stressed-reared pups showed odor avoidance learning and both olfactory bulb and amygdala 2-DG uptake enhancement. Furthermore, stressed-reared pups had elevated CORT levels, and systemic CORT antagonist injection reestablished the age-appropriate odor-preference learning, enhanced olfactory bulb, and attenuated amygdala 2-DG. We also assessed the neural mechanism for stressed-reared pups' abnormal behavior in a more controlled environment by injecting normally reared pups with CORT. This was sufficient to produce odor aversion, as well as dual amygdala and olfactory bulb enhanced 2-DG uptake. Moreover, we assessed a unique cascade of neural events for the aberrant effects of stress rearing: the amygdala-LC-olfactory bulb pathway. Intra-amygdala CORT or intra-LC corticotropin releasing hormone (CRH) infusion supported aversion learning with intra-LC CRH infusion associated with increased olfactory bulb NE (microdialysis). These results suggest that early-life stress disturbs attachment behavior via a unique cascade of events (amygdala-LC-olfactory bulb).

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Figures

Figure 1.
Figure 1.
P7 pups stressed-reared versus normally reared and odor–0.5 mA shock conditioning. A, Number of choices toward the CS odor during the Y-maze test (5 trials). B, Freezing to the conditioned odor presentations (cue test, 5 odor presentations). C, CORT levels immediately after odor–0.5 mA shock conditioning. D–G, 14C 2-DG autoradiography during odor–0.5 mA shock conditioning in the olfactory bulb odor-specific loci of the glomerular layer (D), lateral nucleus of the amygdala (E), basolateral nucleus of the amygdala (F), and central nucleus of the amygdala (G). *p < 0.05, significantly different from the other groups (n = 5–8 per group).
Figure 2.
Figure 2.
Odor–0.5 mA shock conditioning in P7 pups with CORT injection versus saline injection. A, Number of choices toward the CS odor during the Y-maze test (5 trials). B–E, 14C 2-DG autoradiography during odor–0.5 mA shock conditioning in the olfactory bulb odor-specific loci of the glomerular layer (B), lateral nucleus of the amygdala (C), basolateral nucleus of the amygdala (D), and central nucleus of the amygdala (E). F, Pseudocolor 2-DG autoradiography of the olfactory bulb. The odor-specific glomerular layer foci are indicated by arrows and are shown for a control animal on the left and an experimental animal on the right. G, Pseudocolor 2-DG autoradiography of the lateral, basolateral, and central nuclei of the amygdala. *p < 0.05, significantly different from the other groups (n = 5–7 per groups).
Figure 3.
Figure 3.
Odor–0.5 mA shock conditioning in P7 pups with intra-amygdala CORT infusion. A, Number of choices toward the CS odor in a Y-maze test. B, Locations of cannula tips (solid circles) for rats used for CORT infusion into the amygdala (Paxinos et al., 1991). C, Brain section counterstained with cresyl violet illustrating the extent of [3H]CORT diffusion within the amygdala. D, Representative location of cannula tip near the basolateral complex of the amygdala. The cannula tip placement is marked by an arrow. The location of the basolateral complex of the amygdala is illustrated in gray (n = 7–12 per group). *p < 0.05, significantly different from the other groups.
Figure 4.
Figure 4.
Odor–0.5 mA shock conditioning in P7 pups with intra-LC CRH infusion. A, Number of choices toward the CS odor in a Y-maze test. B, Locations of cannula tips (solid circles) for rats used for CRH infusion into the LC. C, Brain section counterstained with cresyl violet illustrating the extent of [3H]CRH diffusion within the LC. D, Representative location of cannula tip near the LC. The cannula tip placement is marked by an arrow. The location of the LC is illustrated in red (n = 6–10 per group). *p < 0.05, significantly different from the other groups.
Figure 5.
Figure 5.
Effect of CRH infusion into the LC on the level of NE measured by microdialysis and HPLC in the olfactory bulb of sensitive-period pups (P7). *p < 0.05, significantly different from the other groups.
Figure 6.
Figure 6.
Schematic illustrating the normal pathway activated by odor-preference learning and the pathway activated by chronic stress. Specifically, chronic stress activates the hypothalamus–pituitary–adrenal axis to release CORT. Consequently, the action of this blood-borne CORT on the amygdala permits CRH release from amygdala efferents to the LC, which releases NE directly into the olfactory bulb.
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