It is commonly accepted that general anesthesia produces unconsciousness and amnesia. However, the extent to which the anesthetized brain receives and retains information is not well understood. Memory of a given event relies upon initial consolidation and subsequent retrieval. In order to test the effects of anesthesia on these separate memory components, we compared what rats reported behaviorally with what their brains 'reported' histologically. In chapter 2, we fully anesthetized rats with ketamine/xylazine anesthesia and exposed the animals to a novel odorant mixture. The following day the rats were presented with the same odorant mixture while awake in order to assess behavioral familiarity. The rats demonstrated no memory of the odorants previously presented during anesthesia. In order to assess odor-induced brain changes, rats were sacrificed for histological analysis 2 hours after exposure to the odorants during anesthesia, or 2 hours after re-exposure while awake the following day. We quantified the protein expression of c-fos, an immediate early gene thought to be critical for memory consolidation, in cortical olfactory regions. During anesthesia, a novel odorant mixture activated c-Fos similar to that found in awake animals. Repeated exposure to the odorants caused an attenuation of c-Fos regardless of whether the initial exposure occurred while anesthetized or awake. This suggests that memory-related protein changes can occur in olfactory cortical regions despite anesthesia. Given, the potential information consolidation observed in these ketamine/xylazine anesthetized animals, we attempted to retrieve olfactory memories using additional behavioral paradigms and memory-enhancing drugs in chapter 3, but were unable to reveal any explicit memory formation. However, we found subtle changes in odorant approach latency, suggesting a potential implicit memory. Further histological investigation in chapter 4 revealed that changes in odor-induced neurogenesis could also occur despite ketamine/xylazine anesthesia, similar to that found with c-Fos labeling, thus supporting the permissive role of this anesthetic. However, odor-related changes in c-Fos did not occur with the anesthetics pentobarbital or propofol, suggesting these traits are not universal amongst all anesthetics. Nevertheless, these data indicate a functional disconnection between the cortical representation of an environmental stimulus and the corresponding perceptual experience or memory.

Altered oligodendrocyte structure and function is implicated in major mental illnesses, including low density and reduced expression of oligodendrocyte-specific gene transcripts in major depressive disorder (MDD). These features are also observed in the unpredictable chronic mild stress (UCMS) and chronic corticosterone (CORT) rodent models of the illness; however, whether oligodendrocyte changes are a causal component of MDD is not known. The oligodendrocyte-specific gene 2-3-cyclic nucleotide-3-phosphodiesterase (CNP1) is a key component of axoglial communication and has previously been implicated in psychiatric disorders. A recent study in our lab found decreased levels of CNP1 in the amygdala (a central region of mood regulation) of human post-mortem MDD subjects and mice exposed to UCMS. In an attempt to determine whether altered CNP1 (or disrupted oligodendrocyte integrity) represents a causal factor in MDD, we investigated MDD-related features in mice lacking CNP1 (CNP1KO mice). In terms of technical development, we: 1) initiated use of a novel Z-score normalization procedure to counteract variability and extract a more comprehensive and translational view of our behavioral analyses, and 2) propose that the fear conditioning paradigm can be used to assess corticolimbic dysfunctions relating to mechanisms of MDD. Together, our studies in CNP1KO mice reveal a surprising profile of behavioral resilience that is accompanied by patterns of amygdala-related dysfunction. In addition, we show robust upregulation of oligodendrocyte and immune related transcripts in the basolateral amygdala of CNP1KO mice. This pattern is suggestive of compensatory changes for oligodendrocyte structure/function and indicative of an association between oligodendrocytes and immune function. Together, these studies demonstrate that disruption of oligodendrocyte function (via CNP1 ablation) can impact circuits mediating emotionality in mice resulting in abnormal affective behaviors. However, downstream molecular changes combined with the observation of longterm detrimental consequences in these mice (e.g. neurodegeneration), is suggestive of a maladaptive role for CNP1 in MDD.

Primary sensory neurons are one of the major components of the peripheral nervous system and are required for collecting and transmitting information regarding the external and internal environment to the central nervous system (CNS). The cell bodies of these neurons are located in peripheral ganglia adjacent to the spinal cord and associated with cranial nerves V, VII, IX and X (cranial nerves I, II, VIII also carry sensory information but have specialized sensory organs that detect specific stimuli). Primary sensory neurons whose cells bodies are found in spinal ganglia (also called dorsal root ganglia (DRG)) have been the focus of intense scientific investigation because of their role in transmitting sensation including those associated with pain and as a model system for understanding mechanisms of development and plasticity. The studies presented in this dissertation focus on the interactions between primary sensory neurons and growth factors that regulate developmental events, as well as adult physiology. In particular, these studies examine sensory neurons that respond to the growth factor neurturin (NRTN), the majority of which innervate the epidermis.

Transcriptional regulation is an important component of the peripheral sensory neuronal response to injury. The transcription factor Sox11 is upregulated in injured dorsal root ganglion (DRG) neurons. Sox11 expression has been linked to neuronal survival and improved regeneration following nerve injury; however, its transcriptional targets are largely unknown. Towards understanding the pro-regenerative effects of Sox11, this dissertation focused on the identification of novel Sox11 transcriptional targets. Targets were initially identified via microarray screening and were validated by approaches including real-time PCR, luciferase reporter assays, western blot and chromatin immunoprecipitation (ChIP). Brain-derived neurotrophic factor (BDNF), adenomatous polyposis coli (APC) and TRAF-associated activator of NF-kappa B (TANK) were identified as putative Sox11 transcriptional targets. BDNF and APC have previously been linked to pro-regenerative pathways in DRG neurons. BDNF is a growth factor that has been shown to increase the intrinsic growth state of neurons (Geremia et al., 2010). APC is a modulator of Wnt signaling pathways and a plus-end microtubule stabilizing protein and been shown to be essential for neurite extension following peripheral axotomy (Zhou et al., 2006). TANK is a novel gene in the context of nerve regeneration signaling; my experiments show that TANK is highly expressed in dissociated DRG neuronal cultures, that TANK knockdown increased apoptosis in Neuro-2a cells following TNF-alpha stimulation and that TANK expression may modulate activation of c-Jun N-terminal kinase (JNK).

Thesis (Ph. D.)--University of Louisville, 2005. / School of Medicine, Department of Anatomical Sciences and Neurobiology. Vita. "May 2005." Includes bibliographical references (leaves 172-186).

Sex differences are widespread throughout the nervous system and have been identified in relation to almost every neural characteristic, from basic anatomy, to behavior, to differences in the prevalence of neuropathology. Most sex differences arise following exposure to the steroid hormone, testosterone, but relatively little is known about the molecular mechanism of steroid hormone action. In many cases, perinatal hormone exposure determines life-long sex specific changes, suggesting a long-lasting cellular memory for the testosterone exposure. Testosterone-induced changes in chromatin structure could account for this memory leading to long-term changes in gene expression. In this dissertation, I tested the hypothesis that chromatin remodeling plays a role in sexual differentiation of brain morphology, neurochemistry and behavior. To test this, I disrupted the balance between histone acetylation and deacetylation using the histone deacetylase inhibitor, valproic acid (VPA), during the critical period for hormone action. First, I determined that VPA treatment increased histone acetylation 24 hours following injection. Next, I revealed that masculinization of BNSTp volume and cell number is blocked by neonatal VPA treatment. I then determined the effect of VPA treatment on cell death in the BNSTp. As expected, females had more dying cells than males. However, VPA treatment had no effect on cell death in either sex. Testosterone treatment reduced cell death in the BNSTp of females and VPA treatment prevented this testosterone-induced cell survival. In the AVPV, females had more TH-positive cells than males but VPA treatment did not affect the number of TH cells in either sex. In the lateral septum, the predicted sex difference was observed; males had more vasopressin-immunoreactive fibers than females. VPA treatment had no effect in males but increased the vasopressin fiber density in females, reducing the sex difference. In addition, males showed a preference for female-soiled bedding whereas females showed a preference for male-soiled bedding. VPA treatment did not alter olfactory preference in males, but decreased preference for male bedding in females, partially masculinizing females. Taken together, these results suggest that regulation of histone acetylation following testosterone exposure plays a role in sexual differentiation of brain morphology, neurochemistry and behavior.

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