Healthy aging is associated with a reduction in slow-wave sleep (SWS), crucial for declarative memory consolidation in young adults; consequently, previously observed benefits of sleep on declarative learning in older adults could reflect a passive role of sleep in protecting memories from waking interference, rather than an active, stabilizing effect. To dissociate the passive and active roles of sleep, a visuo-spatial task was administered; memory was probed after a 12 hr interval consisting of either daytime wake or overnight sleep and post-wake/post-sleep stability of the memories was tested following task-related interference. Ninety five older adults (mean=65.43 yrs; SD=7.6 yrs) and 137 young adults (mean= 21.22yrs; SD=2.62 yrs) were tested across either an “Interference” or a “No Interference” condition (without exposure to the interference). In both young and older adults, sleep significantly benefitted performance compared to wake, such that the memories were more resistant to subsequent interference. For young adults, post-sleep performance was correlated with time spent in SWS and delta power density during SWS early in the night. Additionally, the interaction between NREM and REM early in the night played an important role in stabilizing the memories. There were no significant correlations between sleep parameters and over-sleep performance changes in older adults; however, high performing older adults benefitted from greater amounts of REM sleep early in the night, and from the interaction between NREM and REM during this time period. These results suggest that the active role of sleep in declarative memory consolidation persists in an aging population.

Adolescence is a period of time when the brain undergoes profound development. Myelination is a maturational process in which oligodendroglia project out lipid-rich ramifications which wrap and insulate axons. This is crucial for effective neurotransmission between brain regions and, if compromised by pharmacological insults such as alcohol, can have long-term implications on behavior and cognition. We have previously shown that adolescent alcohol impacts males and females differentially, however it remains unknown how alcohol impacts oligodendroglia during development. The goal of this study was to determine the cellular dynamics of the oligodendroglia in male and female mice through development with and without alcohol exposure. Our results suggest that sexually dimorphic temporal dynamics exist within oligodendroglia. Specifically, this population of cells is notably dynamic during adolescence in males while stable in females. In addition, preliminary studies show that alcohol may cause a restriction on differentiation of oligodendroglia in male but not female mice. Further understanding of sex differences in the mechanisms of alcohol-induced change to oligodendroglia development could create the foundation for targeted, specific therapeutic agents and allow for individualized treatment of patients suffering from alcohol use disorders and potentially other addictions.

Prenatal stress has been correlated with adverse developmental outcomes affecting infant cognition and behavior. Previous studies have shown that prenatal stress can lead to increased susceptibility to adult disease but few studies have looked at the physiological stress response system by measuring the activity of the hypothalamicpituitary-adrenal (HPA) axis. Cortisol, the output of the HPA axis can be secreted in many different matrices (saliva, blood, urine, feces and hair). Most studies that do, only look at one measure of hormone production instead of examining multiple matrices. Additionally these studies do not look at the relationship between matrices. Hair provides a long-term assessment of cortisol hormone production as related to infant behavior. Four measures of cortisol representative of prenatal and postpartum periods were collected in a sample population of rhesus macaques at the NIH facility. No stress was applied to these animals and cortisol concentrations were assessed in maternal hair, infant hair, amniotic fluid, and mothers’ milk. These cortisol measures were then analyzed first to determine vii the relationships between the four measures and second to relate these cortisol values to infant behavior in the primate neonatal neurobehavioral assessment. Subjects of this study were 30 mothers and infants from the 2015 and 2016 breeding cohort. 25 of which, were unique dyads. Using four statistical analyses and 3 groupings of behavior, we found that maternal hair cortisol concentrations were correlated with different temperaments of infants, while milk cortisol concentrations were correlated with infant’s visual exploration of the environment. Additionally, an inverse relationship was found between hair cortisol concentrations and both hair cortisol concentrations with amniotic fluid cortisol. Together, the four statistical analyses show that Maternal HPA axis activation during and after pregnancy affects infant behavioral development 1 month postpartum.

Proper synaptic connectivity is critical for communication between cells and information processing in the brain. Neurons are highly interconnected, forming synapses with multiple partners, and these connections are often refined during the course of development. While decades of research have elucidated many molecular players that regulate these processes, understanding their specific roles can be difficult due to the large number of synapses and complex circuitry in the brain. In this thesis, I investigate mechanisms that establish neural circuits in the simple organism C. elegans, allowing us to address this important problem with single cell resolution in vivo. First, I investigate remodeling of excitatory synapses during development. I show that the immunoglobulin domain protein OIG-1 alters the timing of remodeling, demonstrating that OIG-1 stabilizes synapses in early development but is less critical for the formation of mature synapses. Second, I explore how presynaptic excitatory neurons instruct inhibitory synaptic connectivity. My work shows that disruption of cholinergic neurons alters the pattern of connectivity in partnering GABAergic neurons, and defines a time window during development in which cholinergic signaling appears critical. Lastly, I define novel postsynaptic specializations in GABAergic neurons that bear striking similarity to dendritic spines, and show that presynaptic nrx-1/neurexin is required for the development of spiny synapses. In contrast, cholinergic connectivity with their other postsynaptic partners, muscle cells, does not require nrx-1/neurexin. Thus, distinct molecular signals govern connectivity with these two cell types. Altogether, my findings identify fundamental principles governing synapse development in both the developing and mature nervous system.

Inhibitory GABAergic neurons in the parafacial zone (PZGABA) are essential for slow wave sleep (SWS). Since existing literature about the heterogenous population of PZ neurons is lacking, questions remain regarding the non-GABAergic sleep active PZ neurons. This study seeks to determine if glutamatergic PZ neurons expressing the transcription factor Phox2B (PZPhox2B) participate in sleep-wake control. Phox2B-IRES-Cre mice received injections of adeno-associated virus containing Cre-dependent diphtheria toxin subunit A (DTA) DNA into the PZ (PZPhox2B-DTA). Analysis of injection sites revealed transfection covering the PZ and the locus coeruleus, also known to express Phox2B. We recorded the sleep-wake cycle of PZPhox2B-DTA mice and compared them with control mice, analyzing their sleep-wake quantity, fragmentation, and power spectral distribution. We found total amounts and cortical power for wakefulness, SWS, and REM sleep of PZPhox2B-DTA mice were unaffected. There was fragmentation in wakefulness during the active period for PZPhox2B-DTA mice, seen as a significant reduction in the amount of time and number of episodes spent in the longest bout; however, wakefulness during the rest period was not significantly altered. No significant change was found in the bout numbers and amounts for SWS and REM sleep of PZPhox2B-DTA mice. I was unable to confirm targeted ablation of PZPhox2B-DTA neurons due to a lack of reliable antibody staining. Therefore, it remains possible that ablation of PZPhox2B neurons was incomplete and the wakeful fragmentation is due to neuronal ablation outside of the PZ, such as in the neighboring LC.

No description available.

The anterior cingulate cortex (ACC) is part of the cognitive and emotional brain circuitry that mediates social interaction. Imbalances between inhibitory, GABAergic neurons, and excitatory, glutamatergic neurons, in this region are essential to brain circuity during social responses and are thought to be involved with behaviors associated with autism spectrum disorder (ASD). Enriched cell populations of glutamatergic neurons, obtained through laser capture microdissection, were used for gene expression studies of GABAergic receptors (GABRA1, GABRA4, and GABBR1). Additionally, proteins that impact GABAergic synapses (Spinophilin, CPLX1, mTOR, IGF1R, PSD95, PARP1) were investigated using Western Blotting with punchdissected homogenate brain tissue from ACC and frontal cortical brain regions. No significant differences in gene expression nor protein were identified between ASD and control brain donors. Evidence of GABAergic synaptic pathology was not found; however, future studies of alternative GABAergic markers and increased study numbers are needed to confirm these findings in ASD human tissue.

Neurogenesis is an important and vastly under-explored area in reptiles. While the ability to generate new brain cells in the adult mammalian brain is limited, reptiles are able to regenerate large populations of neuronal cells. Pythons exhibit a characteristic specific dynamic action (SDA) response after food intake with an increase in metabolic rate that facilitates processing the meal. Associated with this change in SDA, pythons (Python spp.) also exhibit impressive plasticity in their digestive and cardiovascular physiology due to the sheer magnitude of the increase in organ growth that occurs after a meal to speed digestion, absorption, and assimilation of nutrients. While this systemic growth in response following food consumption is well documented, whether the python brain exhibits associated changes in cell proliferation following food consumption and digestion is currently unexplored. For this study, juvenile male ball pythons (Python regius) were used to test the hypothesis that postprandial neurogenesis is associated with food consumption. We used the thymidine analog 5-bromo-12’-deoxyuridine (BrdU) to quantify and compare cell proliferation in the brain of fasted snakes and at two time points: two days and six days after a meal, which span time periods of during and after SDA response, respectively. Quantification of BrdU-labeled cells in the ventricular regions relealed that – consistent with other reptile species – the retrobulbar and olfactory regions had the highest numbers of proliferating cells in the python brain, regardless of sampling time. Throughout the telencephalon, cell proliferation was significantly greater in the six-day post-feeding group, with no difference between the two-day post-feeding group and controls. Most other postprandial systemic plasticity occurs within a day or two after a meal and decreases thereafter; however, the brain displays a more delayed response, with a surge of cell proliferation after most of the digestion and absorption is complete. Our results support our hypothesis that food consumption does affect cell proliferation in the python brain, and indicates that the degree of increased proliferation is dependent on the time since feeding.

No description available.

No description available.