Faculty Bibliography

BACKGROUND: The formation of an odor percept in humans is strongly associated with visual information. However, much less is known about the roles of learning and memory in shaping the multisensory nature of odor representations in the brain. METHOD: The dynamics of odor and visual association in olfaction was investigated using three functional magnetic resonance imaging (fMRI) paradigms. In two paradigms, a visual cue was paired with an odor. In the third, the same visual cue was never paired with an odor. In this experimental design, if the visual cue was not influenced by odor-visual pairing, then the blood-oxygen-level-dependent (BOLD) signal elicited by subsequent visual cues should be similar across all three paradigms. Additionally, intensity, a major dimension of odor perception, was used as a modulator of associative learning which was characterized in terms of the spatiotemporal behavior of the BOLD signal in olfactory structures. RESULTS: A single odor-visual pairing cue could subsequently induce primary olfactory cortex activity when only the visual cue was presented. This activity was intensity dependent and was also detected in secondary olfactory structures and hippocampus. CONCLUSION: This study provides evidence for a rapid learning response in the olfactory system by a visual cue following odor and visual cue pairing. The novel data and paradigms suggest new avenues to explore the dynamics of odor learning and multisensory representations that contribute to the construction of a unified odor percept in the human brain.

Fetal alcohol spectrum disorders (FASD) are associated with cognitive and behavioral deficits, and decreased volume of the whole brain and cerebral cortex. Rodent models have shown that early postnatal treatments, which mimic ethanol toxicity in the third trimester of human pregnancy, acutely induce widespread apoptotic neuronal degeneration and permanent behavioral deficits. However, the lasting cellular and anatomical effects of early ethanol treatments are still incompletely understood. This study examined changes in neocortex volume, thickness, and cellular organization that persist in adult mice after postnatal day 7 (P7) ethanol treatment. Post mortem brain volumes, measured by both MRI within the skull and by fluid displacement of isolated brains, were reduced 10-13% by ethanol treatment. The cerebral cortex showed a similar reduction (12%) caused mainly by lower surface area (9%). In spite of these large changes, several features of cortical organization showed little evidence of change, including cortical thickness, overall neuron size, and laminar organization. Estimates of total neuron number showed a trend level reduction of about 8%, due mainly to reduced cortical volume but unchanged neuron density. However, counts of calretinin (CR) and parvalbumin (PV) subtypes of GABAergic neurons showed a striking >30% reduction of neuron number. Similar ethanol effects were found in male and female mice, and in C57BL/6By and BALB/cJ mouse strains. Our findings indicate that the cortex has substantial capacity to develop normal cytoarchitectonic organization after early postnatal ethanol toxicity, but there is a selective and persistent reduction of GABA cells that may contribute to the lasting cognitive and behavioral deficits in FASD.

As is true in all sensory systems, chemosensory perception reflects not only the external stimulus, but also the internal state and past experiences of the perceiver. This means that perception of stable stimulus input may be highly variable as the perceiver's state (e.g., hunger/satiety, fearful/secure, etc.) and experience with the stimulus (e.g., novel/familiar, expected/unexpected) changes. That is, the same basic sensory circuit may produce different outputs depending on internal state and past experience. These changes in sensory coding and circuit function appear to derive from changes in both neuromodulatory tone and from feedback from higher order, non-sensory circuits. While these processes occur in all sensory systems, they may be particularly relevant in the chemical senses which monitor stimuli relevant to nutrition, reproduction, kin recognition and predator avoidance. This symposium will present new data from both the olfactory (Kay, Mandairon, Sadrian) and gustatory (Fontanini) systems exploring how this internal modulation occurs. The talks will include diverse research techniques primarily in awake animals (e.g., single-unit recordings, local field potential recordings, pharmacological and optogenetic manipulations, novel behavioral assays) which examine the role of neuromodulatory systems as well as inputs to primary sensory regions providing feedback information regarding expectation, memory and hedonics. TEST

The thalamus is a key crossroad structure in the brain and is recognized as a major contributor to sensory perception, attention, sleep and arousal and memory. For all senses except olfaction, the information from the sensory neurons necessarily passes through a thalamic nucleus before reaching the primary sensory cortex. However, an olfactory thalamic nucleus exists: the mediodorsal thalamic nucleus (MDT) receives direct input from different olfactory structures including the piriform cortex (PCX), and in turn has bi-directional projections with the orbitofrontal cortex (OFC). Functionally, we have shown that, in urethane-anesthetized rats, MDT units respond to a wide variety of odorants and that odor stimuli induce a conjoint emergence of beta frequency oscillations in both the MDT and the PCX. Beyond this odor responsiveness, the precise role of the MDT in olfaction remains unclear. In fact, lesion studies in both humans and animal models suggest a role for the MDT in olfactory perception, odor discrimination, learning and attention. To investigate precisely the role of the MDT in olfactory processing, we recorded MDT single unit activity, using a multi-tetrode drive, in 8 rats performing a two alternative odor discrimination task. Our preliminary analyses demonstrate that a majority of MDT units modulate their firing rate during the task window. The MDT units seem to encode a variety of information. For example, a subset of MDT units modulate their firing rate before the nose poke/ trial initiation, others show modulation during the sampling period as a function of the odorant, while others are modulated during sampling termination/decision making. Our initial analyzes thus reveal the involvement and the complex role of the MDT in olfactory processing

Episodic memory decline, olfactory identification deficits and the ApoE-e4 allele constitute risk factors for incident Alzheimers' Disease (AD). However, the relationships among these three risk factors are poorly understood, in part due to the paucity of large longitudinal datasets that involve such assessments. The present study used data from the Betula study (n=1225), which involves memory testing every five years. Participants completed an odor identification test, were genotyped for the ApoE gene, and had completed episodic memory testing for a 10-year period (3 testing occasions) leading up to the olfactory assessment. The episodic memory measure was a composite of five tasks, and decline was defined as an estimated change >1SD below the age norm. Participants were thus classified as "decliners" (n=125) or "non-decliners" (n=1100). Results showed that decliners had a poorer olfactory identification than nondecliners. However, when ApoE-e4 was taken into consideration, the association between memory decline and odor identification deficit was only present in ApoE-e4 carriers, whereas odor identification in memory decliners without e4 reached the same level as that of non-decliners. Future research on the role of olfaction in age-related memory impairment and dementia should consider the mediating role played by the ApoE-e4

The rodent piriform cortex (PCX) is a paleocortical structure known to support olfactory perception toward learned behavior. While the anterior PCX is used in associative odor object information decoding, the posterior PCX receives more descending input fibers from brain structures such as the amygdala that are thought to provide a qualitative relevance to raw odor percepts. Here we investigate the influence of top-down influence of specific brain regions on spontaneous and odor-induced activity in the posterior PCX at the single unit level. Using optogenetic techniques, we artificially stimulated descending fibers in the posterior PCX that were virally transduced from one of two interconnected brain regions. Specifically, the lateral and basolateral amygdala (LA/BLA) and the lateral entorhinal cortex (LEC) were independently targeted to express Channelrhodopsin in pyramidal neurons that also express CaMKII. Photostimulation at 473nm and 1mW near infected axon terminals in the posterior piriform was sufficient to drive temporally coincident responses of unit activity and local field potential, as recorded in anaesthetized animals injected at any one of the two target regions. Odorpaired photostimulation of descending fibers at the posterior PCX modulated local single unit response patterns compared to odor only. Photo-induced effects on unit odor responses ranged from suppressive to stimulatory, which often varied depending on the combinatorial timing of odor and light stimulation. These results demonstrate the importance of top-down inputs to piriform cortex in odor coding, and highlight that cortical odor processing takes place in a rich milieu of sensory, emotional and contextual information

Bilateral cortical circuits are not necessarily symmetrical. Asymmetry, or cerebral lateralization, allows functional specialization of bilateral brain regions and has been described in humans for such diverse functions as perception, memory and emotion. There is also evidence for asymmetry in the human olfactory system, though evidence in non-human animal models is lacking. Here, we took advantage of the known changes in olfactory cortical local field potentials that occur over the course of odor discrimination training to test for functional asymmetry in piriform cortical activity during learning. Both the right and left piriform cortex local field potential activities were recorded. The results demonstrate robust inter-hemispheric asymmetry in anterior piriform cortex activity that emerges during specific stages of odor discrimination learning, with a transient bias toward the left hemisphere. This asymmetry is not apparent during error trials. Furthermore, functional connectivity (coherence) between the bilateral anterior piriform cortices is learning- and context-dependent. Steady-state inter-hemispheric anterior piriform cortex coherence is reduced during initial stages of learning and then recovers as animals acquire competent performance. The decrease in coherence is seen relative to bilateral coherence expressed in the home cage, which remains stable across conditioning days. Similarly, transient, trial-related inter-hemispheric coherence increases with task competence. Together the results demonstrate transient asymmetry in piriform cortical function during odor discrimination learning until mastery, and suggests that each PCX may contribute something unique to odor memory

Caregiver-associated cues, including those learned in abusive attachment, provide a sense of safety and security to the child. Here, we explore how cues associated with abusive attachment, such as maternal odor, can modify the enduring neurobehavioral effects of early-life abuse. Two early-life abuse models were used: a naturalistic paradigm, where rat pups were reared by an abusive mother; and a more controlled paradigm, where pups underwent peppermint odor-shock conditioning that produces an artificial maternal odor through engagement of the attachment circuit. Animals were tested for maternal odor preference in infancy, forced swim test (FST), social behavior, and sexual motivation in adulthood-in the presence or absence of maternal odors (natural or peppermint). Amygdala odor-evoked local field potentials (LFPs) via wireless electrodes were also examined in response to the maternal odors in adulthood. Both early-life abuse models induced preference for the maternal odors in infancy. In adulthood, these early-life abuse models produced FST deficits and decreased social behavior, but did not change sexual motivation. Presentation of the maternal odors rescued FST and social behavior deficits induced by early-life abuse and enhanced sexual motivation in all animals. In addition, amygdala LFPs from both abuse animal models showed unique activation within the gamma frequency (70-90 Hz) bands in response to the specific maternal odor present during early-life abuse. These results suggest that attachment-related cues learned during infancy have a profound ability to rescue neurobehavioral dysregulation caused by early-life abuse. Paradoxically, abuse-associated cues seem to acquire powerful and enduring antidepressive properties and alter amygdala modulation.Neuropsychopharmacology advance online publication, 29 October 2014; doi:10.1038/npp.2014.266.

Alzheimer's disease (AD) is a neurodegenerative disorder which is the most common cause of dementia in the elderly today. One of the earliest symptoms of AD is olfactory dysfunction. The present study investigated the effects of amyloid beta precursor protein (AbetaPP) metabolites, including amyloid-beta (Abeta) and AbetaPP C-terminal fragments (CTF), on olfactory processing in the lateral entorhinal cortex (LEC) using the Tg2576 mouse model of human AbetaPP over-expression. The entorhinal cortex is an early target of AD related neuropathology, and the LEC plays an important role in fine odor discrimination and memory. Cohorts of transgenic and age-matched wild-type (WT) mice at 3, 6, and 16months of age (MO) were anesthetized and acute, single-unit electrophysiology was performed in the LEC. Results showed that Tg2576 exhibited early LEC hyperactivity at 3 and 6MO compared to WT mice in both local field potential and single-unit spontaneous activity. However, LEC single-unit odor responses and odor receptive fields showed no detectable difference compared to WT at any age. Finally, the very early emergence of olfactory system hyper-excitability corresponded not to detectable Abeta deposition in the olfactory system, but rather to high levels of intracellular AbetaPP-CTF and soluble Abeta in the anterior piriform cortex (aPCX), a major afferent input to the LEC, by 3MO. The present results add to the growing evidence of AbetaPP-related hyper-excitability, and further implicate both soluble Abeta and non-Abeta AbetaPP metabolites in its early emergence.