Faculty Bibliography

Multisensory integration is particularly important in the human olfactory system, which is highly dependent on non-olfactory cues, yet its underlying neural mechanisms are not well understood. In this study, we use intracranial electroencephalography techniques to record neural activity in auditory and olfactory cortices during an auditory-olfactory matching task. Spoken cues evoke phase locking between low frequency oscillations in auditory and olfactory cortices prior to odor arrival. This phase synchrony occurs only when the participant's later response is correct. Furthermore, the phase of low frequency oscillations in both auditory and olfactory cortical areas couples to the amplitude of high-frequency oscillations in olfactory cortex during correct trials. These findings suggest that phase synchrony is a fundamental mechanism for integrating cross-modal odor processing and highlight an important role for primary olfactory cortical areas in multisensory integration with the olfactory system.

A growing body of evidence shows that olfactory information is processed within a thalamic nucleus in both rodents and humans. The mediodorsal thalamic nucleus (MDT) receives projections from olfactory cortical areas including the piriform cortex (PCX) and is interconnected with the orbitofrontal cortex (OFC). Using electrophysiology in freely moving rats, we recently demonstrated the representation of olfactory information in the MDT and the dynamics of functional connectivity between the PCX, MDT and OFC. Notably, PCX-MDT coupling is specifically increased during odor sampling of an odor discrimination task. However, whether this increase of coupling is functionally relevant is unknown. To decipher the importance of PCX-MDT coupling during the sampling period, we used optogenetics to specifically inactivate the PCX inputs to MDT during an odor discrimination task and its reversal in rats. We demonstrate that inactivating the PCX inputs to MDT does not affect the performance accuracy of an odor discrimination task and its reversal, however, it does impact the rats' sampling duration. Indeed, rats in which PCX inputs to MDT were inactivated during the sampling period display longer sampling duration during the odor reversal learning compared to controls-an effect not observed when inactivating OFC inputs to MDT. We demonstrate a causal link between the PCX inputs to MDT and the odor sampling performance, highlighting the importance of this specific cortico-thalamic pathway in olfaction.

Perceptual learning is an enhancement in discriminability of similar stimuli following experience with those stimuli. Here, we examined the efficacy of adding additional active training following a standard training session, compared with additional stimulus exposure in the absence of associated task performance. Mice were trained daily in an odor-discrimination task, and then, several hours later each day, received 1 of 3 different manipulations: 1) a second active-training session, 2) non-task-related odor exposure in the home cage, or 3) no second session. For home-cage exposure, odorants were presented in small tubes that mice could sniff and investigate for a similar period of time as in the active discrimination task each day. The results demonstrate that daily home-cage exposure was equivalent to active odor training in supporting improved odor discrimination. Daily home-cage exposure to odorants that did not match those used in the active task did not improve learning, yielding outcomes similar to those obtained with no second session. Piriform cortical local field potential recordings revealed that both sampling in the active learning task and investigation in the home cage evoked similar beta band oscillatory activity. Together the results suggest that odor-discrimination learning can be significantly enhanced by addition of odor exposure outside of the active training task, potentially because of the robust activity evoked in the olfactory system by both exposure paradigms. They further suggest that odorant exposure alone could enhance or maintain odor-discrimination abilities in conditions associated with olfactory impairment, such as aging or dementia.

Learning, memory, and emotional regulation are all modulated by sleep. Sleep influences on neural circuit function and plasticity occur in all mammalian brain regions examined to date, including the noncanonical olfactory system, suggesting sleep disruption could have wide-ranging consequences on behavior and cognition. New evidence suggests that sleep disturbances during early development can have particularly insidious and long-lasting consequences. In particular, work from our lab and others suggests that early-life adverse events can disrupt sleep across the life span, thus contributing to a variety of negative cognitive and behavioral outcomes. These findings raise the possibility that interventions targeting sleep may have therapeutic value for children or adults exposed to early-life adverse events. Here, we describe sleep and sleep ontogeny and then describe the role of sleep in normal and pathological brain function. Finally, we explore how early-life adverse events and sleep disturbances may reciprocally interact to produce a range of psychopathological outcomes.
Copyright

The ability to recognize and identify a smell is highly dependent on multisensory context and expectation, for example, hearing the name of the odor source. Here, we develop a novel auditory-odor association task in rats, wherein the animal learn that a specific auditory tone, when associated with a specific odor, predicts reward (Go signal), whereas the same tone associated with a different odor, or vice versa, is not (No-Go signal). The tone occurs prior to the onset of the odor, allowing physiological analyses of sensory-evoked local field potential activity to each stimulus in primary auditory cortex and anterior piriform cortex. In trained animals that have acquired the task, both auditory and subsequent olfactory cues activate beta band oscillations in both the auditory and piriform cortices, suggesting multisensory integration. Naïve animals show no such multisensory responses, suggesting the response is learned. In addition to the learned multisensory evoked responses, functional connectivity between auditory and piriform cortex, as assessed with spectral coherence and phase lag index, is enhanced. Importantly, both the multi-sensory evoked responses and the functional connectivity are context-dependent. In trained animals, the same auditory stimuli presented in the home cage evoke no responses in auditory or piriform cortex, and functional connectivity between the sensory cortices is reduced. Together, the results demonstrate how learning and context shape the expression of multisensory cortical processing. Given that odor identification impairment is associated with preclinical dementia in humans, the mechanisms suggested here may help develop experimental models to assess effects of neuropathology on behavior.Significance statement An important feature in mammalian olfaction is the multisensory support provided by "higher" senses, such as hearing and vision. In humans, such multisensory context and expectation, for example hearing the name of the odor source, facilitates the identification of a smell. An impaired ability to identify odors is a sensitive predictor of cognitive decline and neurodegenerative dementia. We found that rats trained on a tone-odor association task, but not untrained rats, showed elevated electrophysiological responses in both auditory and olfactory cortices, as well as increased functional connectivity between these regions, during task engagement. These results provide evidence of a multisensory integration process that might provide clues to how neuropathology affects the brain.

Neurofilament (NFL) proteins have recently been found to play unique roles in synapses. NFL is known to interact with the GluN1 subunit of N-methyl-D-aspartic acid (NMDAR) and be reduced in schizophrenia though functional consequences are unknown. Here we investigated whether the interaction of NFL with GluN1 modulates synaptic transmission and schizophrenia-associated behaviors. The interaction of NFL with GluN1 was assessed by means of molecular, pharmacological, electrophysiological, magnetic resonance spectroscopy (MRS), and schizophrenia-associated behavior analyses. NFL deficits cause an NMDAR hypofunction phenotype including abnormal hippocampal function, as seen in schizophrenia. NFL-/- deletion in mice reduces dendritic spines and GluN1 protein levels, elevates ubiquitin-dependent turnover of GluN1 and hippocampal glutamate measured by MRS, and depresses hippocampal long-term potentiation. NMDAR-related behaviors are also impaired, including pup retrieval, spatial and social memory, prepulse inhibition, night-time activity, and response to NMDAR antagonist, whereas motor deficits are minimal. Importantly, partially lowering NFL in NFL+/- mice to levels seen regionally in schizophrenia, induced similar but milder NMDAR-related synaptic and behavioral deficits. Our findings support an emerging view that central nervous system neurofilament subunits including NFL in the present report, serve distinctive, critical roles in synapses relevant to neuropsychiatric diseases.

Apolipoprotein E (ApoE) is an important lipid carrier in both the periphery and the brain. The ApoE ε4 allele (ApoE4) is the single most important genetic risk-factor for Alzheimer's disease (AD) while the ε 2 allele (ApoE2) is associated with a lower risk of AD-related neurodegeneration compared to the most common variant, ε 3 (ApoE3). ApoE genotype affects a variety of neural circuits; however, the olfactory system appears to provide early biomarkers of ApoE genotype effects. Here, we directly compared olfactory behavior and olfactory system physiology across all three ApoE genotypes in 6-month- and 12-month-old mice with targeted replacement for the human ApoE2, ApoE3, or ApoE4 genes. Odor investigation and habituation were assessed, along with, olfactory bulb and piriform cortical local field potential activity. The results demonstrate that while initial odor investigation was unaffected by ApoE genotype, odor habituation was impaired in E4 relative to E2 mice, with E3 mice intermediate in function. There was also significant deterioration of odor habituation from 6 to 12 months of age regardless of the ApoE genotype. Olfactory system excitability and odor responsiveness were similarly determined by ApoE genotype, with an ApoE4 > ApoE3 > ApoE2 excitability ranking. Although motivated behavior is influenced by many processes, hyper-excitability of ApoE4 mice may contribute to impaired odor habituation, while hypo-excitability of ApoE2 mice may contribute to its protective effects. Given that these ApoE mice do not have AD pathology, our results demonstrate how ApoE affects the olfactory system at early stages, prior to the development of AD.