Faculty Bibliography

Sleep quality varies widely across individuals, especially during normal aging, with impaired sleep contributing to deficits in cognition and emotional regulation. Sleep can also be impacted by a variety of adverse events, including childhood adversity. Here we examined how early life adverse events impacted later life sleep structure and physiology using an animal model to test the relationship between early life adversity and sleep quality across the life span. Rat pups were exposed to an Adversity-Scarcity model from postnatal day 8-12, where insufficient bedding for nest building induces maternal maltreatment of pups. Polysomnography and sleep physiology were assessed in weaning, early adult and older adults. Early life adversity induced age-dependent disruptions in sleep and behavior, including lifelong spindle decreases and later life NREM sleep fragmentation. Given the importance of sleep in cognitive and emotional functions, these results highlight an important factor driving variation in sleep, cognition and emotion throughout the lifespan that suggest age-appropriate and trauma informed treatment of sleep problems.

Infant maltreatment increases vulnerability to physical and mental disorders, yet specific mechanisms embedded within this complex infant experience that induce this vulnerability remain elusive. To define critical features of maltreatment-induced vulnerability, rat pups were reared from postnatal day 8 (PN8) with a maltreating mother, which produced amygdala and hippocampal deficits and decreased social behavior at PN13. Next, we deconstructed the maltreatment experience to reveal sufficient and necessary conditions to induce this phenotype. Social behavior and amygdala deficits (volume, neurogenesis, c-Fos, local field potential) required combined chronic high corticosterone and maternal presence (not maternal behavior). Hippocampal deficits were induced by chronic high corticosterone regardless of social context. Causation was shown by blocking corticosterone during maltreatment and suppressing amygdala activity during social behavior testing. These results highlight (1) that early life maltreatment initiates multiple pathways to pathology, each with distinct causal mechanisms and outcomes, and (2) the importance of social presence on brain development.

A report in this issue of Acta Physiologica describes how leptin, a hormone released by fat cells in the body, modulates olfactory system neural activity and odor perception in a manner that could promote homeostatic regulation of responses to food odor. The mammalian olfactory system serves dual chemosensory functions. Its classic sensory role is to monitor and identify volatile molecules in the air through orthonasal olfaction or in foods in the mouth through retronasal olfaction. This external chemosensory monitoring drives or modulates diverse behaviors including feeding, mate selection, kin recognition, predator avoidance, and spatial orientation/homing. However, it is now well established that this external monitoring occurs in the context of an internal chemical monitoring of nutritional status, reproductive status, and more general internal state. This article is protected by copyright. All rights reserved.

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.

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

Neonatal brain lesions cause deficits in structure and function of the cerebral cortex that sometimes are not fully expressed until adolescence. To better understand the onset and persistence of changes caused by postnatal day 7 (P7) ethanol treatment, we examined neocortical cell numbers, volume, surface area and thickness from neonatal to post-adolescent ages. In control mice, total neuron number decreased from P8 to reach approximately stable levels at about P30, as expected from normal programmed cell death. Cortical thickness reached adult levels by P14, but cortical volume and surface area continued to increase from juvenile (P20-30) to post-adolescent (P54-93) ages. P7 ethanol caused a reduction of total neurons by P14, but this deficit was transient, with later ages having only small and non-significant reductions. Previous studies also reported transient neuron loss after neonatal lesions that might be partially explained by an acute acceleration of normally occurring programmed cell death. GABAergic neurons expressing parvalbumin, calretinin, or somatostatin were reduced by P14, but unlike total neurons the reductions persisted or increased in later ages. Cortical volume, surface area and thickness were also reduced by P7 ethanol. Cortical volume showed evidence of a transient reduction at P14, and then was reduced again in post-adolescent ages. The results show a developmental sequence of neonatal ethanol effects. By juvenile ages the cortex overcomes the P14 deficit of total neurons, whereas P14 GABA cell deficits persist. Cortical volume reductions were present at P14, and again in post-adolescent ages.

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.

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.