Faculty Bibliography

Prenatal alcohol exposure is the leading nongenetic cause of human intellectual impairment. The long-term impacts of prenatal alcohol exposure on health and well-being are diverse, including neuropathology leading to behavioral, cognitive, and emotional impairments. Additionally negative effects also occur on the physiological level, such as the endocrine, cardiovascular, and immune systems. Among these diverse impacts is sleep disruption. In this review, we describe how prenatal alcohol exposure affects sleep, and potential mechanisms of those effects. Furthermore, we outline the evidence that sleep disruption across the lifespan may be a mediator of some cognitive and behavioral impacts of developmental alcohol exposure, and thus may represent a promising target for treatment.

Infant survival relies on rapid identification, remembering and behavioral responsiveness to caregivers' sensory cues. While neural circuits supporting infant attachment learning have largely remained elusive in children, use of invasive techniques has uncovered some of its features in rodents. During a 10-day sensitive period from birth, newborn rodents associate maternal odors with maternal pleasant or noxious thermo-tactile stimulation, which gives rise to a preference and approach behavior towards these odors, and blockade of avoidance learning. Here we review the neural circuitry supporting this neonatal odor learning, unique compared to adults, focusing specifically on the early roles of neurotransmitters such as glutamate, GABA (Gamma-AminoButyric Acid), serotonin, dopamine and norepinephrine, in the olfactory bulb, the anterior piriform cortex and amygdala. The review highlights the importance of deepening our knowledge of age-specific infant brain neurotransmitters and behavioral functioning that can be translated to improve the well-being of children during typical development and aid in treatment during atypical development in childhood clinical practice, and the care during rearing of domestic animals.

In many species, including mice, female animals show markedly different pup-directed behaviours based on their reproductive state^1,2. Naive wild female mice often kill pups, while lactating female mice are dedicated to pup caring^3,4. The neural mechanisms that mediate infanticide and its switch to maternal behaviours during motherhood remain unclear. Here, on the basis of the hypothesis that maternal and infanticidal behaviours are supported by distinct and competing neural circuits^5,6, we use the medial preoptic area (MPOA), a key site for maternal behaviours^7-11, as a starting point and identify three MPOA-connected brain regions that drive differential negative pup-directed behaviours. Functional manipulation and in vivo recording reveal that oestrogen receptor α (ESR1)-expressing cells in the principal nucleus of the bed nucleus of stria terminalis (BNSTpr^ESR1) are necessary, sufficient and naturally activated during infanticide in female mice. MPOA^ESR1 and BNSTpr^ESR1 neurons form reciprocal inhibition to control the balance between positive and negative infant-directed behaviours. During motherhood, MPOA^ESR1 and BNSTpr^ESR1 cells change their excitability in opposite directions, supporting a marked switch of female behaviours towards the young.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by a repeat expansion mutation in the promotor region of the FMR1 gene resulting in transcriptional silencing and loss of function of fragile X messenger ribonucleoprotein 1 protein (FMRP). FMRP has a well-defined role in the early development of the brain. Thus, loss of the FMRP has well-known consequences for normal cellular and synaptic development leading to a variety of neuropsychiatric disorders including an increased prevalence of amygdala-based disorders. Despite our detailed understanding of the pathophysiology of FXS, the precise cellular and circuit-level underpinnings of amygdala-based disorders is incompletely understood. In this review, we discuss the development of the amygdala, the role of neuromodulation in the critical period plasticity, and recent advances in our understanding of how synaptic and circuit-level changes in the basolateral amygdala contribute to the behavioral manifestations seen in FXS.

Developmental exposure to ethanol is a leading cause of cognitive, emotional and behavioral problems, with fetal alcohol spectrum disorder (FASD) affecting more than 1:100 children. Recently, comorbid sleep deficits have been highlighted in these disorders, with sleep repair a potential therapeutic target. Animal models of FASD have shown non-REM (NREM) sleep fragmentation and slow-wave oscillation impairments that predict cognitive performance. Here we use a mouse model of perinatal ethanol exposure to explore whether reduced sleep pressure may contribute to impaired NREM sleep, and compare the function of a brain network reported to be impacted by insomnia-the Salience network-in developmental ethanol-exposed mice with sleep-deprived, saline controls. Mice were exposed to ethanol or saline on postnatal day 7 (P7) and allowed to mature to adulthood for testing. At P90, telemetered cortical recordings were made for assessment of NREM sleep in home cage before and after 4 h of sleep deprivation to assess basal NREM sleep and homeostatic NREM sleep response. To assess Salience network functional connectivity, mice were exposed to the 4 h sleep deprivation period or left alone, then immediately sacrificed for immunohistochemical analysis of c-Fos expression. The results show that developmental ethanol severely impairs both normal rebound NREM sleep and sleep deprivation induced increases in slow-wave activity, consistent with reduced sleep pressure. Furthermore, the Salience network connectome in rested, ethanol-exposed mice was most similar to that of sleep-deprived, saline control mice, suggesting a sleep deprivation-like state of Salience network function after developmental ethanol even without sleep deprivation.

BACKGROUND:In the short term, parental presence while a human infant is in pain buffers the immediate pain responses, although emerging evidence suggests repeated social buffering of pain may have untoward long-term effects. METHODS/FINDING/UNASSIGNED:To explore the short- and long-term impacts of social buffering of pain, we first measured the infant rat pup's [postnatal day (PN) 8, or 12] response to mild tail shock with the mother present compared to shock alone or no shock. Shock with the mother reduced pain-related behavioral activation and USVs of pups at both ages and reduced Fos expression in the periaqueductal gray, hypothalamic paraventricular nucleus, and the amygdala at PN12 only. At PN12, shock with the mother compared to shock alone differentially regulated expression of several hundred genes related to G-protein-coupled receptors (GPCRs) and neural development, whereas PN8 pups showed a less robust and less coherent expression pattern. In a second set of experiments, pups were exposed to daily repeated Shock-mother pairings (or controls) at PN5-9 or PN10-14 (during and after pain sensitive period, respectively) and long-term outcome assessed in adults. Shock+mother pairing at PN5-9 reduced adult carrageenan-induced thermal hyperalgesia and reduced Fos expression, but PN10-14 pairings had minimal impact. The effect of infant treatment on adult affective behavior showed a complex treatment by age dependent effect. Adult social behavior was decreased following Shock+mother pairings at both PN5-9 and PN10-14, whereas shock alone had no effect. Adult fear responses to a predator odor were decreased only by PN10-14 treatment and the infant Shock alone and Shock+mother did not differ. CONCLUSIONS/SIGNIFICANCE/CONCLUSIONS:Overall, integrating these results into our understanding of long-term programming by repeated infant pain experiences, the data suggest that pain experienced within a social context impacts infant neurobehavioral responses and initiates an altered developmental trajectory of pain and affect processing that diverges from experiencing pain alone.

Fragile X Syndrome (FXS) is a neurodevelopmental disorder and the most common monogenic cause of intellectual disability, autism spectrum disorders (ASDs) and anxiety disorders. Loss of fragile x mental retardation protein (FMRP) results in disruptions of synaptic development during a critical period (CP) of circuit formation in the basolateral amygdala (BLA). However, it is unknown how these alterations impact microcircuit development and function. Using a combination of electrophysiologic and behavioral approaches in both male (Fmr1-/y) and female (Fmr1-/-) mice, we demonstrate that principal neurons (PNs) in the Fmr1KO BLA exhibit hyperexcitability during a sensitive period in amygdala development. This hyperexcitability contributes to increased excitatory gain in fear-learning circuits. Further, synaptic plasticity is enhanced in the BLA of Fmr1KO mice. Behavioral correlation demonstrates that fear-learning emerges precociously in the Fmr1KO mouse. Early life THIP intervention ameliorates fear-learning in Fmr1KO mice. These results suggest that CP plasticity in the amygdala of the Fmr1KO mouse may be shifted to earlier developmental timepoints.SIGNIFICANCE STATEMENTIn these studies we identify early developmental alterations in principal neurons in the FXS BLA. We show that as early as P14, excitability and feed-forward excitation, and synaptic plasticity is enhanced in Fmr1KO lateral amygdala. This correlates with precocious emergence of fear-learning in the Fmr1KO mouse. Early life THIP intervention restores CP plasticity in WT mice and ameliorates fear-learning in the Fmr1KO mouse.

The complex process of regulating physiological functions and homeostasis during external and internal disruptions develops slowly in altricial species, with parental care functioning as a co-regulator of infant physiological and emotional homeostasis. Here, we review our current understanding of the infant's use of parental behaviors for neurobehavioral regulation and its disruption with harsh parental care. Taking a cross-species view, we briefly review the human developmental literature that highlights the importance of the caregiver in scaffolding the child's physiological and emotional regulation, especially under threat and stress. We then use emerging corresponding animal literature within the phylogenetically preserved attachment system to help define neural systems supporting caregiver regulation and its supporting causal mechanism to provide translational bridges to inform causation and mechanisms impossible to define in children. Next, we briefly review animal research highlighting the impact of specific sensory stimuli imbedded in parental care as important for infant physiological and emotion regulation. We then highlight the importance of parental sensory stimuli gaining hedonic value to go beyond simple sensory stimuli to further impact neurobehavioral regulation, with poor quality of care compromising the infant's ability to use these cues for regulation. Clinically, parental regulation of the infant is correlated with later-life neurobehavioral outcome and quality of life. We suggest an understanding of this parental regulation of the infant's immediate neurobehavioral functioning within the context of attachment quality, that may provide insights into the complex processes during early life, initiating the pathway to pathology.

Current clinical literature and supporting animal literature have shown that repeated and profound early-life adversity, especially when experienced within the caregiver-infant dyad, disrupts the trajectory of brain development to induce later-life expression of maladaptive behavior and pathology. What is less well understood is the immediate impact of repeated adversity during early life with the caregiver, especially since attachment to the caregiver occurs regardless of the quality of care the infant received including experiences of trauma. The focus of the present manuscript is to review the current literature on infant trauma within attachment, with an emphasis on animal research to define mechanisms and translate developmental child research. Across species, the effects of repeated trauma with the attachment figure, are subtle in early life, but the presence of acute stress can uncover some pathology, as was highlighted by Bowlby and Ainsworth in the 1950s. Through rodent neurobehavioral literature we discuss the important role of repeated elevations in stress hormone corticosterone (CORT) in infancy, especially if paired with the mother (not when pups are alone) as targeting the amygdala and causal in infant pathology. We also show that following induced alterations, at baseline infants appear stable, although acute stress hormone elevation uncovers pathology in brain circuits important in emotion, social behavior, and fear. We suggest that a comprehensive understanding of the role of stress hormones during infant typical development and elevated CORT disruption of this typical development will provide insight into age-specific identification of trauma effects, as well as a better understanding of early markers of later-life pathology.

Social interaction deficits seen in psychiatric disorders emerge in early-life and are most closely linked to aberrant neural circuit function. Due to technical limitations, we have limited understanding of how typical versus pathological social behavior circuits develop. Using a suite of invasive procedures in awake, behaving infant rats, including optogenetics, microdialysis, and microinfusions, we dissected the circuits controlling the gradual increase in social behavior deficits following two complementary procedures-naturalistic harsh maternal care and repeated shock alone or with an anesthetized mother. Whether the mother was the source of the adversity (naturalistic Scarcity-Adversity) or merely present during the adversity (repeated shock with mom), both conditions elevated basolateral amygdala (BLA) dopamine, which was necessary and sufficient in initiating social behavior pathology. This did not occur when pups experienced adversity alone. These data highlight the unique impact of social adversity as causal in producing mesolimbic dopamine circuit dysfunction and aberrant social behavior.