Faculty Bibliography

We are rapidly advancing toward an understanding of the molecular events underlying odor transduction, mechanisms of spatiotemporal central odor processing, and neural correlates of olfactory perception and cognition. A thread running through each of these broad components that define olfaction appears to be their dynamic nature. How odors are processed, at both the behavioral and neural level, is heavily dependent on past experience, current environmental context, and internal state. The neural plasticity that allows this dynamic processing is expressed nearly ubiquitously in the olfactory pathway, from olfactory receptor neurons to the higher-order cortex, and includes mechanisms ranging from changes in membrane excitability to changes in synaptic efficacy to neurogenesis and apoptosis. This review will describe recent findings regarding plasticity in the mammalian olfactory system that are believed to have general relevance for understanding the neurobiology of memory

To support nipple attachment and huddling, rat pups must learn to approach and prefer maternal odor. Similar to other altricial species, rat pups have a sensitive period for learning this odor preference, which ends around postnatal day (PN) 10 and coincides with the emergence of walking. One characteristic of this sensitive period is that an odor paired with moderate shock elicits an odor preference. After PN10, this behavioral training produces an odor aversion, although pain threshold remains unchanged. Recently, we demonstrated that the endogenous opioid system might be a key element in the acquisition of the shock-induced odor preference during the sensitive period since antagonism of this system disrupts odor preference learning. In older pups, acquisition of a shock-induced odor aversion was unaffected by opioid system manipulation. The purpose of these experiments was to further elucidate the role of opioids in infant olfactory learning through assessment of memory consolidation and expression during and after the sensitive period. In Experiment 1, we demonstrate that naltrexone (NTX), a nonspecific opioid antagonist, given immediately following odor-shock conditioning during the sensitive period, blocks odor preference formation and yields an odor aversion. However, the same treatment does not disrupt consolidation of an odor aversion in older pups. In Experiment 2, we demonstrate that during the sensitive period, NTX disrupts expression of the shock-induced odor preference, but not the learned odor aversion in older pups. Results using this model of attachment suggest that opioids have an important role in the acquisition, consolidation, and expression of early olfactory preferences. Furthermore, since prenatal drug exposure is known to alter the endogenous opioid system, these results highlight the capacity of prenatal opiate exposure to disrupt early infant learning and attachment

The present series of experiments assessed how information from the whiskers controls and modulates infant rat behavior during early learning and attachment. Passive vibrissal stimulation can elicit behavioral activity in pups throughout the first two postnatal weeks, although orienting to the source of stimulation is evident only after ontogenetic emergence of whisking. In addition, while pups were capable of demonstrating learning in a classical conditioning paradigm pairing vibrissa stimulation with electric shock, no corresponding changes were detected in the anatomy of the barrel cortex as determined by cytochrome oxidase (CO) staining. Finally, the role of whiskers in a more naturalistic setting was determined in postnatal day (PN)3-5 and PN11-12 pups. Our results showed that both nipple attachment and huddling were disrupted in whisker-clipped PN3-5 pups but only marginally altered in PN1I 1-12 pups. Together, these results suggest that the neonatal whisker system is behaviorally functional and relevant for normal mother-infant interactions, though it lacks the sophistication of a mature whisker system that evokes very specific and directed responses

Clinical data suggests a strong negative impact of traumatic attachments on adult mental illness, presumably through organizing brain development. To further explore this clinical issue, a mammalian model of imprinting was developed to characterize the neural basis of attachment in both healthy and traumatic attachments. The altricial neonatal rat must learn the mother's odor for nipple attachment, huddling, and orienting to the mother, all of which are required for pup survival. While it appears maladaptive to depend upon learning for attachment, the unique learning system of neonatal pups greatly enhances odor-preference learning and attachment while pups are confined to the nest. This heightened learning is expressed behaviorally as an enhanced ability to acquire learned odor preferences and a decreased ability to acquire learned odor aversions. Specifically, both odor-milk and odor-shock (0.5 mA) conditioning result in odor-preference acquisition. It appears as though there are at least three brain structures underlying the neonatal rat's sensitive period for heightened odor learning: (1) odor learning is encoded in the olfactory bulb; (2) the hyperfunctioning noradrenergic locus coeruleus (LC) appears to support preference conditioning through release of NE; and (3) the hypofunctioning amygdala appears to underlie pups' difficulty in learning odor aversions. Overall, this suggests that the CNS of altricial infants is specialized for optimizing attachments to their caregiver

We assessed the neurochemical basis of olfactory learning induced by presentations of odor and moderate shock in infant rats. Paradoxically, shock conditioning produces an odor preference in 8-day-olds, but an odor aversion in 12-day-olds. Studies have demonstrated the importance of opioids in early olfactory learning; their specific role remains undefined. In this study, postnatal Days 8 and 12 pups were systemically injected with naltrexone, a nonspecific opioid antagonist, or saline and received either paired or backward presentations of odor-moderate shock or odor-only presentations. Blocking the opioid system during conditioning disrupted acquisition of the Day 8 odor preference, but not the Day 12 odor aversion. Additional Day 8 pups were given naltrexone posttraining. Naltrexone not only blocked consolidation of an odor preference but also yielded an odor aversion. These results suggest that the opioid system has a critical role in both olfactory learning and consolidation of odor preferences during the sensitive period.

The central nervous system of altricial infants is specialized for optimizing attachments to their caregiver. During the first postnatal days, infant rats show a sensitive period for learning and are particularly susceptible to learning an attraction to their mother's odor. Classical conditioning appears to underlie this learning that is expressed behaviorally as an increased ability to acquire odor preferences and a decreased ability to acquire odor aversions. Specifically, in neonatal rats, pairing an odor with moderately painful shock (0.5mA) or milk produces a subsequent relative preference for that odor. The neural circuitry supporting the increased ability to acquire odor preferences appears to be the heightened functioning of the noradrenergic pontine nucleus locus coeruleus. Indeed, norepinephrine from the locus coeruleus appears to be both necessary and sufficient for learning during the sensitive period. On the other hand, the decreased ability to acquire odor aversions seems to be due to the lack of participation of the amygdala in at least some aversive learning situations. The site of plasticity in the pup's brain appears to be limited to the olfactory bulb. This neonatal sensitive period for learning ends around postnatal day 9-10, at which time pups make the transition from crawling to walking and classical conditioning becomes 'adultlike.' The neonatal behavioral and neural induced changes are retained into adulthood where it modifies sexual behavior

These experiments examined the sufficiency of pairing an odor with either intrabulbar activation of noradrenergic beta-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 beta-receptor activation limited to the olfactory bulb (isoproterenol, 50 microM) displayed a conditioned approach response on subsequent exposure to that odor. Furthermore, putative stimulation of the locus coeruleus (2 microM 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 beta-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