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Behav Neurosci. Author manuscript; available in PMC 2007 June 5.
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Association of an Odor with Activation of Olfactory Bulb Noradrenergic β-Receptors or Locus Coeruleus Stimulation is Sufficient to Produce Learned Approach Responses to that Odor in Neonatal Rats
R. M. Sullivan, G. Stackenwalt, F. Nasr, C. Lemon, and D. A. Wilson
Department of Zoology, University of Oklahoma.
Correspondence concerning this article should be addressed to R. M. Sullivan, Department of Zoology, University of Oklahoma, Norman, Oklahoma 73019. Electronic mail may be sent to rsullivan/at/ou.edu.
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Abstract
These experiments examined the sufficiency of pairing an odor with either intrabulbar activation of noradrenergic β-receptors or pharmacological stimulation of the locus coeruleus to support learned odor preferences in Postnatal Day 6-7 rat pups. The results showed that pups exposed to odor paired with β-receptor activation limited to the olfactory bulb (isoproterenol, 50 μM) displayed a conditioned approach response on subsequent exposure to that odor. Furthermore, putative stimulation of the locus coeruleus (2 μM idazoxan or 2 mM acetylcholine) paired with odor produced a subsequent preference for that odor. The effects of locus coeruleus stimulation could be blocked by a pretraining injection of the β-receptor antagonist propranolol (20 mg/kg). Together these results suggest that convergence of odor input with norepinephrine release from the locus coeruleus terminals within the olfactory bulb is sufficient to support olfactory learning.
Infant rat recognition of maternal odors is dependent on olfactory memory. Infant rat pups demonstrate a sensitive period for learning behavioral approach responses to novel odors associated with stimulation normally received from the dam and littermates (Sullivan & Wilson, 1995; Woo & Leon, 1987). The sensitive period and learned odor responses are critical to maintain the mother-infant interaction necessary for pup survival.
This sensitive period, extending from at least birth to the middle of the second postnatal week, is characterized by a heightened probability of learning odor approach responses and a decreased probability of learning avoidance responses (Blozovski & Cudennec, 1980; Camp & Rudy, 1988; Collier, Mast, Meyer, & Jacobs, 1979; Myslivecek, 1997; Stehower & Campbell, 1980; Sullivan & Wilson, 1995), as well as by specific learning-associated neural changes within the olfactory system (Sullivan & Wilson, 1995; Woo & Leon, 1987). It has been hypothesized that this early neurobehavioral sensitive period may be due to unique characteristics of the neonatal noradrenergic nucleus locus coeruleus (Sullivan & Wilson, 1994). The locus coeruleus projects heavily to the olfactory bulb (Shipley, Halloran, & de la Torre, 1985) and, in neonates, is particularly responsive to stimuli delivered by the dam, such as tactile stimulation (Nakamura, Kimura, & Sakaguchi, 1987). Previous work has demonstrated that the locus coeruleus and activation of olfactory bulb noradrenergic β-receptors is necessary for acquisition of both the conditioned behavioral odor approach response and the modified olfactory bulb response to the learned odor (Price, Darby-King, Harley, & McLean, 1998; Sullivan, McGaugh, & Leon, 1991; Sullivan, Wilson, & Leon, 1989). For example, blockade of noradrenergic β-receptors within the bulb (Sullivan, Zyzak, Skierkowski, & Wilson, 1992) or bilateral lesions of the locus coeruleus (Sullivan, Wilson, Lemon, & Gerhardt, 1994) prevent acquisition of learned odor responses. Norepinephrine β-receptor blockade after acquisition, however, does not impair expression of previously learned behaviors (Sullivan & Wilson, 199la). These results suggest that activation of the noradrenergic projection from the locus coeruleus to the olfactory bulb is necessary for early olfactory learning.
However, although preventing a noradrenergic surge from occurring within the olfactory bulb during odor exposure disrupts olfactory learning, these results do not demonstrate that pairing an odor with an olfactory bulb noradrenergic surge is sufficient to support acquisition of a learned behavioral response. For example, if olfactory bulb changes are just one of several distributed changes that together are required for expression of a learned behavior, then blocking changes in the bulb may be sufficient to disrupt normal learning (as previously demonstrated), whereas inducing change limited to the olfactory bulb may be insufficient to support learning. Similar arguments can be made regarding the role of the locus coeruleus in early learning.
The present experiments, therefore, were an attempt to determine the sufficiency of pairing an odor with either activation of noradrenergic β-receptors solely within the olfactory bulb or with direct locus coeruleus stimulation to support early olfactory learning. Putative locus coeruleus stimulation was accomplished with indwelling cannulas aimed at the locus coeruleus to allow infusion of either acetylcholine, which directly stimulates locus coeruleus neurons (Adams & Foote, 1988) or with idazoxan, a noradrenergic α-2 receptor antagonist, which releases locus coeruleus neurons from autoinhibition and increases locus coeruleus activity (Adams & Foote, 1988; Cedarbaum & Aghajanian, 1976; Kimura & Nakamura, 1987; Sara & Devauges, 1989).
Subjects
The subjects were male and female rat pups born of Long Evans rats (Harlan Sprague Dawley, Indianapolis, IN) in the vivarium at the University of Oklahoma. No more than 1 male and 1 female from a litter were used in an experimental condition. Dams were housed in rectangular polypropylene cages (34 × 29 × 17 cm) lined with wood chips in a temperature and light-controlled room. Ad-lib food and water were available at all times. Births were checked twice daily. The day of birth was considered to be Postnatal Day 0 (PNO).
Cannula Implants
On PN4-5, pups were anesthetized with hypothermia or methoxyflurane (Metofane; Schering-Plough, Union, NJ) and placed in a stereotaxic apparatus with bregma and lambda in approximately the same horizontal plane. Bilateral stainless steel cannulas (30-gauge tubing) were implanted through holes drilled in the skull. Cannulas were placed in either the olfactory bulb granule cell layer-periventricular core or near the locus coeruleus. The olfactory bulbs were located by visual inspection of the immature skull surface, and cannulas were placed at approximately the anterior-posterior midpoint. Locus coeruleus cannulas were directed at 1.4 mm posterior to lambda, 0.6 mm lateral to the midline, and 5.5 mm ventral to the skull surface. The cannula assembly was attached to the skull with dental acrylic. To ensure patency of the cannulas, guide wires were placed in the lumen of the tubing until training. Additional details of cannula implants are provided in Sullivan et al. (1992). After complete recovery from anesthesia (< 30 min), pups were returned to the dam and littermates for a 2-day recovery period before behavioral conditioning.
Drug Manipulations
During behavioral training on PN6-7, cannulas were attached with PE10 tubing to Hamilton 10-μl syringes in a Harvard syringe pump. The olfactory bulb cannulas were filled (0.5 μl/min) with isoproterenol (0, 50, and 100 μM) in saline. The locus coeruleus cannulas were filled with either the noradrenergic α-2 antagonist idazoxan (0, 1, and 2 μM) or acetylcholine (0 and 2 mM) in saline. For both pups with olfactory bulb cannulas and those with locus coeruleus cannulas, the infusion was then continued during the 20-min behavioral training session (10-min habituation period and 10-min training period) at a reduced rate of 0.1 μl/min (to avoid tissue damage) for a total infusion volume of 2 μl. Each pup received a single infusion with a single dose of a single drug.
In one experiment, pups were also injected intraperitoneally with the noradrenergic β-receptor antagonist propranolol (20 mg/kg) 30 min prior to the behavioral training session. Pups were injected and returned to the home cage until training (Sullivan et al., 1989).
Behavioral Training and Testing
Behavioral training occurred on PN6-7, 2 days after cannula implantation. Training involved odor exposure in a temperature-controlled (30 ± 1 °C) Plexiglas container, open at the top to allow odor to be ventilated and to allow tubing connecting the syringe pumps to the cannulas to move freely. Odor stimulation was presented by applying 0.25 μ1 of odorant (peppermint or citral) to a 2.5-cm2 square piece of Kimwipe tissue, suspended above the top of the open training chamber. For data presented in Figures Figures11Figure 1 and and3,3Figure 3, the conditioned odor was citral and for Figure 2Figure 2 the conditioned odor was peppermint.
Figure 1
Figure 1
Figure 1
Pups exposed to odor during intrabulbar infusion of isoproterenol demonstrated a subsequent relative preference (approach) response to that odor. No drugs were infused during the behavioral test that occurred 24 hr after training. Values are means ± (more ...)
Figure 3
Figure 3
Figure 3
Pups exposed to odor during peri-locus coeruleus infusions of acetylcholine (ACh, 2 mM) demonstrated a subsequent relative preference (approach) response to that odor. No drugs were infused during the behavioral test that occurred 24 hr after training. (more ...)
Figure 2
Figure 2
Figure 2
Pups exposed to odor during peri-locus coeruleus infusions of the α-2 antagonist idazoxan demonstrated a subsequent relative preference (approach) response to that odor. No drugs were infused during the behavioral test that occurred 24 hr after (more ...)
Pups were placed in the training chamber and drug infusions were initiated with no odor present for a 10-min habituation period, followed by a 10-min odor exposure period. Drug infusion was maintained during the entire 20-min session. The odor was then removed, tubing disconnected from the cannulas, and the pups returned to the home cage.
Relative odor preference testing was done the following day in a two-odor choice test (Sullivan et al., 1989). Pups were placed in a rectangular arena, with the conditioned odor placed under the wire mesh floor on one side of the arena and clean wood chips (as used in the home cage) on the other side. A 2-cm-wide neutral zone divided the two odors. Pups were placed in the neutral zone and the time spent over each odor was monitored with a videotracking device (Coulbourn Instruments, Allentown, PA). Each pup received three 1-min test sessions, separated by 5-s rests. No drugs were infused through cannulas or injected systemically on the day of behavioral testing.
Histology
After behavioral testing, pups were overdosed with urethane and perfused through the heart with saline and 4% (vol/vol) formalin. Brains were postfixed in 4% formalin and 30% (wt/vol) sucrose. Coronal sections (40 μ) were cut, stained with cresyl violet, and locus coeruleus cannula placements charted.
Association of odor exposure with activation of olfactory bulb noradrenergic β-receptors is sufficient to produce a subsequent relative odor preference in neonatal rat pups (Figure 1Figure 1). Pups with intraolfactory bulb infusions of isoproterenol during odor exposure demonstrated a relative preference for that odor in a subsequent two-odor choice test (no drugs infused during test). Acquisition of the odor preference occurred in a dose-dependent manner, with moderate levels of stimulation producing a strong relative preference and low or high levels not supporting acquisition: analysis of variance (ANOVA), F(2, 27) = 4.22, p < .05. Post hoc Fisher tests revealed pups infused with 50 μ-M isoproterenol (n = 8) were significantly different from vehicle pups (n = 13), whereas pups infused with 100 μM (n = 9) were intermediate and not significantly different from either. This inverted U-shaped dose-response curve is similar to that reported for systemic isoproterenol injections or similar manipulations in pups (Sullivan et al., 1989,1991).
Two methods were used for putative chemical stimulation of the locus coeruleus. First, application of noradrenergic α-2 antagonists releases locus coeruleus neurons from autoinhibition and enhances levels of cortical norepinephrine levels in adults (Adams & Foote, 1988; Cedarbaum & Aghajanian, 1976; Kimura & Nakamura, 1987). Although in rat pups this α-2-mediated autoinhibition is attenuated (Kimura & Nakamura, 1987), α-2 receptors are present and functional on locus coeruleus neurons at birth (Kimura & Nakamura, 1987; Morris, Dausse, Devynck, & Meyer, 1980). Thus, in one series of rat pups, we associated odor exposure with infusion of the specific α-2 antagonist idazoxan into the region of the locus coeruleus (Sara & Devauges, 1989).
Association of an odor with idazoxan infusions near the locus coeruleus produced a subsequent (24 hr posttraining) dosedependent learned preference for that odor (Figure 2Figure 2; no drugs were infused during testing). Pups receiving an infusion of 2 μM idazoxan near the locus coeruleus spent significantly more time over the conditioned odor in the two-odor choice test than all other groups: ANOVA, F(3, 26) = 3.80, p < .05. Post hoc Fisher tests revealed that pups infused with 2 jtM idazoxan (n = 9) were significantly different from vehicle-infused pups (n = 9) and from pups receiving no infusion (n = 4), whereas pups receiving 1 μM infusions (n = 8) were intermediate and did not differ significantly from any other group. In addition to the group receiving vehicle only infusions, a fourth group had cannula implants but did not receive any infusion. The noninfusion pups did not differ significantly in their odor preference from the vehicle controls, thus the infusion alone into this region did not interfere with normal pup behavior.
The second method for putative locus coeruleus stimulation involved infusion of acetylcholine. Acetylcholine and acetylcholine receptor agonists are effective locus coeruleus stimulants in adult rats (Adams & Foote, 1988; Jiang, Griff, Ennis, Zimmer, & Shipley, 1996). Association of odor with 2-mM acetylcholine infusions near the locus coeruleus produced a subsequent (24 hr posttraining) relative learned preference for that odor compared with vehicle-infused pups (Figure 3Figure 3; no drugs were infused during testing). This acetylcholine-induced odor preference could be blocked by systemic injection of the noradrenergic μ-receptor antagonist propranolol (20 mg/kg) during training: ANOVA, F(2, 15) = 4.26, p < .05, suggesting that this learning was mediated by norepinephrine release from the locus coeruleus. Post hoc Fisher tests revealed that pups that received acetylcholine infusion and saline injections (n < 8) were significantly different from both vehicle-infused, saline-injected pups (n = 4) and acetylcholine-infused, propranolol-injected pups (n = 6). Time spent over the neutral zone was not significantly different between groups, suggesting no difference in generalized activity levels: acetylcholine-saline mean = 30.4 ± 7.6 s, acetylcholine-propranolol mean = 34.5 ± 10.6 s, saline-saline mean = 31.3 ± 9.9 s; F(2, 15) = 0.06.
Cannula tip placements for cannulas directed at the locus coeruleus in the acetylcholine experiment are shown in Figure 4Figure 4. All tip placements were less than 1 mm from the locus coeruleus.
Figure 4
Figure 4
Figure 4
Locations of cannula tips (solid circles) in rats used for the experiment shown in Figure 3Figure 3. The locus coeruleus is depicted in gray and highlighted by the horizontal arrows. Distance from bregma for each coronal section is denoted on the right, as taken (more ...)
The present results suggest that association of odor with a surge of norepinephrine from the locus coeruleus to the olfactory bulb is sufficient to produce a subsequent relative preference for that odor in rat pups. Pairing an odor with either direct activation of noradrenergic β-receptors within the olfactory bulb or with putative direct pharmacological stimulation of the locus coeruleus produces a subsequent relative odor preference in a dose-dependent manner.
Although the effects of idazoxan and acetylcholine infusions on locus coeruleus neural activity were not directly assessed in these freely moving, PN6-7 rat pups, several lines of evidence suggest that, in fact, the observed results are due to locus coeruleus activation and norepinephrine release in the olfactory bulb. First, the effects of putative chemical stimulation of the locus coeruleus with acetylcholine could be blocked by systemic injection of a noradrenergic β-receptor antagonist, strongly suggesting that these effects were in fact mediated by locus coeruleus activation. Second, both α-2 adenoreceptors and acetylcholine muscarinic receptors are present on locus coeruleus neurons at the ages examined here (Coyle & Yamamura, 1976; Morris et al., 1980). Third, previous work using the same infusion rates and volumes showed drug diffusion at significant concentrations in a 2-3-mm diameter volume of brain tissue (Sullivan et al., 1992). Given the cannula placements, the infusions reported here would have produced significant concentrations of drugs at the locus coeruleus. Fourth, local infusion of acetylcholine in the adult rat locus coeruleus increases olfactory bulb norepinephrine levels by nearly 250% (El-Etri, Ennis, Griff, & Shipley, 1999). Finally, intraolfactory bulb infusions of the β-receptor antagonist propranolol are sufficient to block learned odor preferences in neonates (Sullivan et al., 1992). This series of observations leads to the conclusion that association of an odor with locus coeruleus activation-induced norepinephrine release in the olfactory bulb is sufficient to produce a subsequent relative preference for that odor in rat pups.
The inverted U-shaped dose-response curve for olfactory bulb isoproterenol infusion effects on subsequent odor preferences is similar to that reported for other pharmacological manipulations in pups (Pedersen, Williams, & Blass, 1982; Sullivan et al., 1989, 1991). Precise mechanisms of inverted U-shaped dose-response curves are unknown, but may include activation of a different population of low affinity receptors at higher concentrations or interaction with other transmitter systems at higher concentrations (e.g., Price et al., 1998; Trombley & Shepherd, 1992).
Noradrenergic Mechanisms of Infant Learning
On the basis of previous work, a series of events has been hypothesized to be involved in infant olfactory learning underlying recognition of maternal odors (Sullivan & Wilson, 1994). Maternal odor activates specific spatial patterns of olfactory bulb mitral-tufted cells via olfactory receptor neurons. Concurrently, other stimuli produced by the mother, such as tactile stimulation, warmth, and milk activate the locus coeruleus (Nakamura et al., 1987) and increase norepinephrine levels in the neonatal olfactory bulb (Rangel & Leon, 1995). Norepinephrine release from locus coeruleus terminals within the olfactory bulb reduces granule cell-mediated inhibition, increases mitral-tufted cell excitability, and reduces mitral-tufted cell habituation to odors (Jiang et al., 1996; Okutani, Yagi, & Kaba, 1999; Trombley & Shepherd, 1992; Wilson & Leon, 1988a; Wilson & Sullivan, 1991, 1992). In neonates, both the reduced inhibition and increased excitability are mediated by noradrenergic β-receptors (Wilson & Leon, 1988a; Wilson & Sullivan, 1991). The combination of spatial patterns of odor-evoked mitral-tufted cell activity with norepinephrineinduced increases in mitral-tufted cell excitability produce long-term changes in mitral-tufted response patterns on subsequent exposure to that odor (Leon, 1987; Sullivan & Wilson, 1994). Experience with the odor in the absence of norepinephrine results in mitral-tufted cell habituation and no long-term changes (Wilson & Sullivan, 1992; Wilson, Sullivan, & Leon, 1987). The learning-associated change in olfactory bulb output response patterns is highly correlated with the magnitude of the learned approach response to that odor (Wilson & Leon, 1988b) and is believed to contribute to that behavioral response. Similar mechanisms have been proposed to underlie odor-induced pregnancy block in the mouse accessory olfactory bulb (Brennan & Keverne, 1997).
The present results strongly support this hypothesized mechanism and demonstrate a critical role for interaction between the locus coeruleus and olfactory bulb in infant olfactory learning. Furthermore, they demonstrate a fundamental role of the olfactory bulb in storing these early olfactory memories. The results suggest that association of odor stimulation and norepinephrine activation in the olfactory bulb alone is sufficient to support olfactory learning. Thus, either the information necessary for odor memory is stored within the olfactory bulb itself, or the combination of odor and norepinephrine produce unique olfactory bulb output patterns during training (Wilson & Sullivan, 1992) that are sufficient to store odor memory in other brain regions (Kucharski & Hall, 1987).
Odor Approach Responses
Rat pups at this age can learn either approach or avoidance responses to odors depending on the training paradigm (Camp & Rudy, 1988; Kucharski & Spear, 1984; Sullivan & Wilson, 1991b; 1995). Thus, because two opposite behavioral responses are possible, the present results raise the question as to why pups learn to specifically approach odors that have been paired with olfactory bulb noradrenergic β-receptor activation. That is, in the absence of any specific information regarding the hedonic valence of the unconditioned stimulus, why do pups appear to assume the conditioned odor is something to be approached?
This assumption by the pups (or default approach response) may be due to the adaptive importance for the pup of maintaining contact with the dam. Identification and localization of the dam and her nipples are critical for pup survival and are largely mediated by learned olfactory cues. We hypothesize that odors with acquired significance are “tagged” by unique response patterns in the olfactory bulb (Wilson et al, 1987). In the absence of additional information, the default behavioral response to tagged stimuli during the first week of life is to approach, given that under natural conditions the vast majority (if not all) of learned odors during that time are of the mother and littermates. Reliance on default approach behavior may change during the second postnatal week as the pup becomes more mobile and may leave the nest (Camp & Rudy, 1988; Sullivan & Wilson, 1995), allowing it to develop more flexible, stimulus-appropriate behaviors. In fact, inhibitory conditioning and passive avoidance begin to emerge around PN10-11 (Blozovski & Cudennec, 1980; Collier et al., 1979; Goldman & Tobach, 1967; Stehower & Campbell, 1980; for review, see Myslivecek, 1997) and preexposure to the conditioned stimulus facilitates conditioning in infant rats, whereas it retards conditioning in weanling and adult rats (Hoffmann & Spear, 1989). Thus, it is predicted that in older or mature animals, odors associated with an olfactory bulb norepinephrine surge may not be differentially responded to in the absence of additional information elsewhere in the brain.
Footnotes
This work was supported by Grant HD33402 from the National Institute of Child Health and Human Development and Grant DC03906 from the National Institute on Deafness and Other Communication Disorders.
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