Faculty Bibliography

The mediodorsal thalamus (MDT) is a higher-order corticocortical thalamic nucleus involved in cognition and memory. However, anatomically, the MDT is also the primary site of olfactory representation in the thalamus, receiving strong inputs from olfactory cortex and having reciprocal connections with orbitofrontal cortex (OFC). Nonetheless, its role in olfaction remains unclear. Here, we recorded single units in the MDT, as well as local field potentials in the MDT, piriform cortex (PCX), and OFC in rats performing a two-alternative odor discrimination task. We show that subsets of MDT units display odorant selectivity during sampling, as well as encoding of spatio-motor aspects of the task. Furthermore, the olfactory trans-thalamic network rapidly switches functional connectivity between MDT and cortical areas depending on current task demands, with, for example, MDT-PCX coupling enhanced during odor sampling and MDT-OFC coupling enhanced during the decision/goal approach compared with baseline and presampling. These results demonstrate MDT representation of diverse sensorimotor components of an olfactory task. SIGNIFICANCE STATEMENT: The mediodorsal thalamus (MDT) is the major olfactory thalamic nucleus and links the olfactory archicortex with the prefrontal neocortex. The MDT is well known to be involved in higher-order cognitive and memory functions, but its role in olfaction is poorly understood. Here, using single-unit and local field potential analyses, we explored MDT function during an odor-guided decision task in rats. We describe MDT odor and multisensory coding and demonstrate behavior-dependent functional connectivity within the MDT/sensory cortex/prefrontal cortex network. Our results suggest a rich representation of olfactory and other information within MDT required to perform this odor-guided task. Our work opens a new model system for understanding MDT function and exploring the important role of MDT in cortical-cortical communication.

Organisms are surrounded throughout life by chemically complex odors. How individuals process an odorant within a mixture or a mixture as a whole is a key question in neuroethology and chemical senses. This question is addressed here by using newborn rabbits, which can be rapidly conditioned to a new stimulus by single association with the mammary pheromone. After conditioning to ethyl maltol (odorant B), pups behaviorally respond to B and an A'B' mixture (68/32 ratio) but not to ethyl isobutyrate (odorant A) or an AB mixture (30/70 ratio). This suggests elemental and configural perception of A'B' and AB, respectively. We then explored the neural substrates underlying the processing of these mixtures with the hypothesis that processing varies according to perception. Pups were pseudoconditioned or conditioned to B on postnatal day 3 before exposure to B, A'B' or AB on day 4. Fos expression was not similar between groups (mainly in the olfactory bulb and posterior piriform cortex) suggesting a differential processing of the stimuli that might reflect either stimulus complexity or conditioning effect. Thus, the ratio of components in A'B' vs AB leads to differential activation of the olfactory system which may contribute to elemental and configural percepts of these mixtures. In addition, together with recent behavioral data, this highlights that configural perception occurs even in relatively immature animals, emphasizing the value of the newborn rabbit for exploration of odor mixture processing from molecules to brain and behavior.

The varepsilon4 allele of the Apolipoprotein E gene is a genetic risk factor for late-onset dementia of the Alzheimers' type (DAT), which is characterized by loss of both episodic memory and olfactory functions. Little is known about the possible role of varepsilon4 in the association between ongoing episodic memory decline and olfactory deficits in the general population, but such information is relevant in determining the relevance of olfaction as a marker of DAT risk. The present study was based on a large, population-based sample (n=1087, aged 45-90 years, of which 324 were varepsilon4-carriers). Episodic memory change rates were established using data collected every 5 years for a 10-20 year interval leading up to an olfactory assessment using the Scandinavian Odor Identification Test at the last wave of data collection. Participants were classified according to whether or not their episodic memory ability declined more rapidly than the age-typical norm (by >1SD). Our main result is that only in varepsilon4-carriers was episodic memory decline associated with odor identification impairment. In individuals without varepsilon4, odor identification was unrelated to episodic memory decline status. Follow-up analyses indicated that this moderation by varepsilon4 was due to the olfactory nature of the identification test, and that the effect was not caused by 63 individuals with dementia. Our results suggest that the varepsilon4 determines the functional association between ongoing episodic memory decline and olfaction. These findings are consistent with the notion that varepsilon4-carriers with DAT, compared to non-carriers, display a cortical atrophy pattern that is more focused on mediotemporal lobe regions supporting olfactory and episodic memory functions. Olfactory and memory assessments might provide complementary information on mediotemporal atrophy prior to clinical dementia onset, but the varepsilon4 should be considered when using olfactory assessment as an early-stage indicator.

Developmental ethanol exposure can lead to long-lasting cognitive impairment, hyperactivity, and emotional dysregulation among other problems. In healthy adults, sleep plays an important role in each of these behavioral manifestations. Here we explored circadian rhythms (activity, temperature) and slow-wave sleep in adult mice that had received a single day of ethanol exposure on postnatal day 7 and saline littermate controls. We tested for correlations between slow-wave activity and both contextual fear conditioning and hyperactivity. Developmental ethanol resulted in adult hyperactivity within the home cage compared to controls but did not significantly modify circadian cycles in activity or temperature. It also resulted in reduced and fragmented slow-wave sleep, including reduced slow-wave bout duration and increased slow-wave/fast-wave transitions over 24 hour periods. In the same animals, developmental ethanol exposure also resulted in impaired contextual fear conditioning memory. The impairment in memory was significantly correlated with slow-wave sleep fragmentation. Furthermore, ethanol treated animals did not display a post-training modification in slow-wave sleep which occurred in controls. In contrast to the memory impairment, sleep fragmentation was not correlated with the developmental ethanol-induced hyperactivity. Together these results suggest that disruption of slow-wave sleep and its plasticity are a secondary contributor to a subset of developmental ethanol exposure's long-lasting consequences.

In the present study, we tested whether the volatile metabolome was altered by mutations of the Alzheimer's disease (AD)-implicated amyloid precursor protein gene (APP) and comprehensively examined urinary volatiles that may potentially serve as candidate biomarkers of AD. Establishing additional biomarkers in screening populations for AD will provide enhanced diagnostic specificity and will be critical in evaluating disease-modifying therapies. Having strong evidence of gross changes in the volatile metabolome of one line of APP mice, we utilized three unique mouse lines which over-express human mutations of the APP gene and their respective non-transgenic litter-mates (NTg). Head-space gas chromatography/mass spectrometry (GC/MS) of urinary volatiles uncovered several aberrant chromatographic peak responses. We later employed linear discrimination analysis and found that the GC/MS peak responses provide accurate (>84%) genotype classification of urinary samples. These initial data in animal models show that mutant APP gene expression entails a uniquely identifiable urinary odor, which if uncovered in clinical AD populations, may serve as an additional biomarker for the disease.

Olfactory information is synthesized within the olfactory cortex to provide not only an odor percept, but also a contextual significance that supports appropriate behavioral response to specific odor cues. The piriform cortex serves as a communication hub within this circuit by sharing reciprocal connectivity with higher processing regions, such as the lateral entorhinal cortex and amygdala. The functional significance of these descending inputs on piriform cortical processing of odorants is currently not well understood. We have employed optogenetic methods to selectively stimulate lateral and basolateral amygdala (BLA) afferent fibers innervating the posterior piriform cortex (pPCX) to quantify BLA modulation of pPCX odor-evoked activity. Single unit odor-evoked activity of anesthetized BLA-infected animals was significantly modulated compared with control animal recordings, with individual cells displaying either enhancement or suppression of odor-driven spiking. In addition, BLA activation induced a decorrelation of odor-evoked pPCX ensemble activity relative to odor alone. Together these results indicate a modulatory role in pPCX odor processing for the BLA complex. This interaction could contribute to learned changes in PCX activity following associative conditioning, as well as support alternate patterns of odor processing that are state-dependent.

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.

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

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

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