Faculty Bibliography

The roots of psychopathology frequently take shape during infancy in the context of parent-infant interactions and adversity. Yet, neurobiological mechanisms linking these processes during infancy remain elusive. Here, using responses to attachment figures among infants who experienced adversity as a benchmark, we assessed rat pup cortical local field potentials (LFPs) and behaviors exposed to adversity in response to maternal rough and nurturing handling by examining its impact on pup separation-reunion with the mother. We show that during adversity, pup cortical LFP dynamic range decreased during nurturing maternal behaviors, but was minimally impacted by rough handling. During reunion, adversity-experiencing pups showed aberrant interactions with mother and blunted cortical LFP. Blocking pup stress hormone during either adversity or reunion restored typical behavior, LFP power, and cross-frequency coupling. This translational approach suggests adversity-rearing produces a stress-induced aberrant neurobehavioral processing of the mother, which can be used as an early biomarker of later-life pathology.

Current non-invasive neuroimaging methods can assess neural activity in all areas of the human brain but the olfactory bulb (OB). The OB has been suggested to fulfill a role comparable to that of V1 and the thalamus in the visual system and have been closely linked to a wide range of olfactory tasks and neuropathologies. Here we present a method for non-invasive recording of signals from the human OB with millisecond precision. We demonstrate that signals obtained via recordings from EEG electrodes at the nasal bridge represent responses from the human olfactory bulb - recordings we term Electrobulbogram (EBG). The EBG will aid future olfactory-related translational work but can also potentially be implemented as an everyday clinical tool to detect pathology-related changes in human central olfactory processing in neurodegenerative diseases. In conclusion, the EBG is localized to the OB, is reliable, and follows response patterns demonstrated in non-human animal models.

Olfactory identification impairment might indicate future cognitive decline in elderly individuals. An unresolved question is to what extent this effect is dependent on the ApoE-ε4, a genotype associated with risk of Alzheimer's Disease (AD). Given the current concern about reproducibility in empirical research, we assessed this issue in a large sample (n = 1637) of older adults (60 - 96 years) from the population-based longitudinal Swedish National Study on Aging and Care in Kungsholmen (SNAC-K). A hierarchical regression analysis was carried out to determine if a low score on an odor identification test, and the presence of ApoE-ε4, would predict the magnitude of a prospective 6-year change in the Mini-Mental State Examination (MMSE) after controlling for demographic, health-related, and cognitive variables. We found that overall, lower odor identification performance was predictive of cognitive decline, and, as hypothesized, we found that the effect was most pronounced among ApoE-ε4 carriers. Our results from this high-powered sample suggest that in elderly carriers of the ApoE-ε4 allele, odor identification impairment provides an indication of future cognitive decline, which has relevance for the prognosis of AD.

The affective state is the combination of emotion and mood, with mood reflecting a running average of sequential emotional events together with an underlying internal affective state. There is now extensive evidence that odors can overtly or subliminally modulate mood and emotion. Relying primarily on neurobiological literature, here we review what is known about how odors can affect emotions/moods and how emotions/moods may affect odor perception. We take the approach that form can provide insight into function by reviewing major brain regions and neural circuits underlying emotion and mood, and then reviewing the olfactory pathway in the context of that emotion/mood network. We highlight the extensive neuroanatomical opportunities for odor-emotion/mood convergence, as well as functional data demonstrating reciprocal interactions between these processes. Finally, we explore how the odor- emotion/mood interplay is, or could be, used in medical and/or commercial applications.

Most odors are not composed of a single volatile chemical species, but rather are mixtures of many different volatile molecules, the perception of which is dependent on the identity and relative concentrations of the components. Changing either the identity or ratio of components can lead to shifts between configural and elemental perception of the mixture. For example, a 30/70 ratio of ethyl isobutyrate (odorant A, a strawberry scent) and ethyl maltol (odorant B, a caramel scent) is perceived as pineapple by humans - a configural percept distinct from the components. In contrast, a 68/32 ratio of the same odorants is perceived elementally, and is identified as the component odors. Here, we examined single-unit responses in the anterior and posterior piriform cortex (aPCX and pPCX) of mice to these A and B mixtures. We first demonstrate that mouse behavior is consistent with a configural/elemental perceptual shift as concentration ratio varies. We then compared responses to the configural mixture to those evoked by the elemental mixture, as well as to the individual components. Hierarchical cluster analyses suggest that in the mouse aPCX, the configural mixture was coded as distinct from both components, while the elemental mixture was coded as similar to the components. In contrast, mixture perception did not predict pPCX ensemble coding. Similar electrophysiological results were also observed in rats. The results suggest similar perceptual characteristics of the AB mixture across species, and a division in the roles of aPCX and pPCX in the coding of configural and elemental odor mixtures.

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.

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.

Child development research highlights caregiver regulation of infant physiology and behavior as a key feature of early life attachment, although mechanisms for maternal control of infant neural circuits remain elusive. Here we explored the neurobiology of maternal regulation of infant fear using neural network and molecular levels of analysis in a rodent model. Previous research has shown maternal suppression of amygdala-dependent fear learning during a sensitive period. Here we characterize changes in neural networks engaged during maternal regulation and the transition to infant self-regulation. Metabolic mapping of 2-deoxyglucose uptake during odor-shock conditioning in postnatal day (PN)14 rat pups showed that maternal presence blocked fear learning, disengaged mesolimbic circuitry, basolateral amygdala (BLA), and plasticity-related AMPA receptor subunit trafficking. At PN18, when maternal presence only socially buffers threat learning (similar to social modulation in adults), maternal presence failed to disengage the mesolimbic dopaminergic system, and failed to disengage both the BLA and plasticity-related AMPA receptor subunit trafficking. Further, maternal presence failed to block threat learning at PN14 pups following abuse, and mesolimbic dopamine engagement and AMPA were not significantly altered by maternal presence-analogous to compromised maternal regulation of children in abusive relationships. Our results highlight three key features of maternal regulation: (1) maternal presence blocks fear learning and amygdala plasticity through age-dependent suppression of amygdala AMPA receptor subunit trafficking, (2) maternal presence suppresses engagement of brain regions within the mesolimbic dopamine circuit, and (3) early-life abuse compromises network and molecular biomarkers of maternal regulation, suggesting reduced social scaffolding of the brain.