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The ability of migrating neurons and growth cones to navigate through their environment is crucial for the correct development of the brain. Cells and growth cones may be guided by electrical, chemical or topographical cues in their environment. Pax6 is a transcription factor vital for brain development. Pax6-/- mutant mice die perinatally with defects in neuronal proliferation and differentiation, cortical cell migration and axon guidance, yet it is not clear which guidance cues Pax6-/- mutant neurons fail to interpret. Dissociated cultured cells were used to study the cell-autonomous effects of Pax6 mutation on guidance of growth cones and migrating neural precursors by environmental cues. Neurites from mouse embryonic cortical neurons aligned perpendicular to 1 μm-wide, 130 nm-deep substratum grooves. Pax6-/- mutation abolished contact-mediated neurite guidance by these grooves. Laminin induced a switch from perpendicular to parallel alignment to grooves, via a β1 integrin-independent mechanism. Blocking cAMP signalling abolished perpendicular alignment to polylysine-coated grooves, but enhanced parallel alignment to laminin-coated grooves. Pax6 null mutation or overexpression also caused specific defects in contact-guided migration by cortical cells. An electric field applied to E16.5 cortical neurons increased the frequency of extension of neurites aligned perpendicular to the field axis. Pax6-/- mutant cells responded to an electric field with reduced anodal extension, but no significant increase in perpendicular neurite extension. Electrical cues were prioritised over topographical cues when presented in combination. Taken together, data suggest that Pax6 mutant cortical cells do not completely lack the ability to detect extracellular guidance cues, but they respond differently to wild-type cells. In combination with other defects identified in the cortex, this may contribute to the cell migration and axon guidance phenotypes in the brain of the Pax6-/- embryo. This study also identified novel Pax6 expression in the trigeminal ganglion, where it may regulate axon guidance and neurogenesis.

It has long been acknowledged that inhibitory interneurons play a crucial role in regulating the input-output functions of principal cells in the hippocampus. The investigations we conducted focus on one specific population of interneurons, expressing the protein parvalbumin. The thesis describes three different studies, aimed to characterize anatomical and functional aspects of parvalbumin positive interneurons in the mouse hippocampal formation. The first study examines long-range projections of these neurons from CA1 and subiculum to distant regions of the brain, finding potential targets mainly in septal, thalamic and hypothalamic areas. The second study investigates the role of parvalbumin-positive interneurons of the dentate gyrus in spatial memory. Behavioural experiments with radial arm and Morris water maze have been carried out to understand how these GABAergic interneurons regulate information flow during reference and working memory. Finally, a third study describes basic anatomical features of parvalbuminpositive dendritic spines in the dentate gyrus. Their characteristics have been widely studied in principal neurons but little is known about spines in interneurons. Here I show a peculiar distribution of spines on apical dendrites of these cells, with a predominant localization within the inner third of the molecular layer. All studies utilized a combination of transgenic Cre-expressing mice and Creactivatable AAVs. For the first and third study AAV-based neuronal labeling was applied to visualize neurons, including their projections and their spines, respectively, through expression of fluorescent proteins. For the second study instead two genetic tools have been used in order to disrupt the neurotransmission from parvalbuminpositive interneurons and examine the effects on behavioral task performance.

1 / Amanda Rosemary Pahng

acase@tulane.edu / Women are at greater risk to develop the incurable psychiatric diseases posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). In spite of the elevated risk associated with female biological sex, the vast majority of preclinical studies have exclusively used male rodents. Therefore, the neurobiology which underlies the increased susceptibility to stress-related mental illness associated with female sex is largely unknown. Currently, it is thought that regulation of the transcription factor cyclic-AMP response element binding protein (CREB) may act as a molecular locus capable of transducing aversive experiences into lasting changes in the structure and function of neurons in the hippocampus. However, the signal transduction cascades recruited by stress to modulate CREB activity are less well understood. Therefore, the goal of this thesis was to investigate stress-induced modulation of CREB phosphorylation and upstream signaling cascades in the hippocampus of male and female rodents exposed to severe stress. Exposure to either acute predator odor stress or chronic variable stress reduced phosphorylation of CREB in the male, but not the female hippocampus. Predator odor exposure rapidly reduced phosphorylation of extracellular signal-regulated kinase and increased nuclear expression of the synapto-nuclear messenger protein Jacob in the male hippocampus, consistent with the previously described CREB shut-off cascade. Chronic variable stress affected the activity of Sirtuin1, a metabolically-sensitive deacetylase known to interact with CREB, in the male, but not the female dentate gyrus sub-area of the hippocampus, possibly through recruitment of adenosine monophosphate activated protein kinase. Behaviorally, female rodents exposed to predator odor exhibited an impaired ability to discriminate between a context previously paired with the predator odor and a neutral context, possibly representing a fear over-generalizing phenotype. In contrast female rodents exposed to chronic variable stress did not exhibit the altered metabolic phenotypes observed in male rodents exposed to chronic variable stress, suggesting that females are more resilient to chronic stress. Collectively, these data suggest that the female hippocampus resists changes in CREB phosphorylation associated with severe stress which may contribute to sex differences observed in stress-related mental health disorders. / 1 / Damek Homiack

Non-pathological decline in memory is a pervasive process during aging. One common age-associated condition that is linked to cognitive dysfunction is inflammation. In particular, cellular signaling via the nuclear factor kappa B pathway (NFκB), which regulates inflammation, is up-regulated during the aging process but its precise role in learning and memory across the lifespan is not fully understood. The purpose of the experiments in this dissertation were to investigate the role of NFκB in age-associated cognitive decline and to determine factors that mediate cognitive decline during aging in conditions with up-regulated NFκB signaling. To achieve these aims, young, middle-aged and aged rats were tested on a hippocampus-dependent memory task and levels of NFκB were compared between age groups and individual differences in NFκB levels were correlated with memory. In young mice, inflammation was induced via dextran sulfate sodium, and levels of NFκB and memory were compared between groups and individual variation in NFκB was correlated with behavior. Lastly, using the Midlife Development in the United States data set, the psychosocial variables that predict cognitive decline with age were examined in relation to inflammatory status. The results from this dissertation provide insight into the co-variation of NFκB signaling and cognition across the lifespan and identify important personal and experiential factors that may alter this relationship. / 1 / Andrea F Jones