Neuroscience and Behavior Dissertations Collection

Lateralization of central circadian pacemaker output

Mahoney, Carrie E — Wed, 16 Jan 2013 12:24:55 PST

The suprachiasmatic nucleus of the hypothalamus (SCN) contains a master pacemaker that controls a wide variety of circadian rhythms of physiology and behavior. Recent work has provided a thorough understanding of the molecular mechanisms by which these oscillations are generated. The rhythmic expression of clock genes is essential to pacemaker function. These clock genes are also expressed rhythmically throughout the mammalian organism including peripheral organs and brain regions outside of the SCN. Synchronization within these tissues and maintenance of phase angle between the different systems depends upon the integrity of the SCN. The present experiments will focus on the nature of the SCN-dependent signals responsible for the entrainment of peripheral oscillations. Such signals may be neural, humoral, or behavioral, and various organs may rely on different signals or a combination of such signals. The first specific aim will test the importance of neuronal vs. humoral signals in the regulation of peripheral oscillator phase. The asymmetrical haPer1 expression in the SCN of Syrian hamsters held in constant light that show split locomotor behavior will be used to determine if a similar level of asymmetry of clock gene expression in the left and right sides of the body in bilaterally paired organs is accomplished by lateralized neuronal projections of the SCN. Asymmetrical expression of physiologically important genes in these peripheral organs will also be assessed. Specific aim 2 will determine if a molecular clock oscillates within arousal-promoting neurons, specifically the hypocretin-expressing neurons of the LH/DMH and the tyrosine hydroxylase-expressing cells of the locus coeruleus. Specific Aim 3 will utilize the behaviorally split Syrian hamster to determine if lateralized projections from the SCN control the phase of clock gene expression within these arousal-promoting neurons.^

Gradients and Ranges of Visually Selective Attention Based on Location, Objects, Color, and Size: Gradients are Universal, but Range is Uniquely Spatial

Bush, William S. — Tue, 11 Dec 2012 11:39:00 PST

Two interesting properties of the distribution of spatially selective attention have been noted in the behavioral and electrophysiological literature. First, there is a graded field of attention that expands from the center of the attended area. Second, the size of the attended area can be adjusted to be either larger or smaller in order to match the demands of the current task. Five event-related potential (ERP) studies are presented that extend these findings in several important ways; 1) The time frame of these two distribution properties is different. Results are consistent with a two stage model of spatial attention in which visual processing is initially enhanced for all stimuli presented near the center of the attended area as indexed by the amplitude of the first negative peak in the waveform (N1). Subsequently, the effects of narrowing or expanding the attentional field to the relevant size affects visual processing as indexed by the amplitude of the second negative peak (N2). 2) Object boundaries had limited impact on either the spread of the initial gradient of spatial selection or the scale of attention. 3) When selecting visual stimuli for attentive processing based on features such as color and size there is also a gradient of facilitation, but the impact of this graded selection on visual processing is not observed until later in processing, and is indexed by the amplitude of the selection negativity (SN). Furthermore, similar to the lack of interaction between object boundaries and the range of cued locations, the gradients of feature-based selection are not affected by the range of cued features.

Analysis of Morgue, a novel ubiquitination protein that functions in programmed cell death

Zhou, Ying — Mon, 24 Sep 2012 11:00:51 PDT

The Drosophila morgue gene was identified as a regulator of programmed cell death and protein ubiquitination. It has been shown to enhance programmed cell death via promoting the turnover of DIAP1, a conserved anti-apoptotic protein. Morgue protein contains a zinc finger motif, an F box domain and a ubiquitin E2 conjugase variant domain with a Cysteine to Glycine substitution at the catalytic site. This unique domain/motif architecture suggests that Morgue may have very distinctive activities. However, how and what each domain/motif contributes to Morgue function remains unexplored. My dissertation project focused on a study of Morgue protein evolution and function using a combination of bioinformatics, genetics and biochemical methods. The results suggest that Morgue exhibits widespread but restricted phylogenetic distribution among invertebrate metazoans; the study of Morgue's origin provides an example of how multi-domain proteins may evolve. Results of functional studies revealed that over-expression of Morgue can induce a homozygous lethal phenotype that is independent of either F-box or the Glycine in the UEV domain. In addition, co-immunoprecipitation experiments have shown that Morgue associates with SkpA and Lys48 linked polyubiquitin chains, indicating that Morgue might be a multi-functional protein in PCD and ubiquitination. ^

Attentional Cues During Speech Perception

Best, Lori Astheimer — Tue, 06 Dec 2011 08:35:59 PST

Temporally selective attention allows for the preferential processing of stimuli presented at particular times, and is reasoned to be important for processing rapidly presented information such as speech. Recent event-related potential (ERP) evidence demonstrates that listeners direct temporally selective attention to times that contain word onsets in speech. This may be an effective listening strategy since these moments provide critical information to the listener, but the mechanism that underlies this process remains unexplored. In three experiments, putative attention cues including word recognition and predictability were manipulated in both artificial and natural speech and ERP responses at various times were compared to determine how listeners selectively process word onsets in speech. The results demonstrate that listeners allocate attention to word-initial segments because they are less predictable than other times in the speech stream. Attending to unpredictable moments may improve spoken language comprehension by allowing listeners to glean the most relevant information from an otherwise overwhelming speech signal.

Novel Progestin Signaling Molecules in the Brain: Distribution, Regulation and Molecular Mechanism of Action

Intlekofer, Karlie A. — Fri, 19 Aug 2011 08:51:38 PDT

Progesterone regulates female reproduction in many ways, yet it is still unclear how signals are conveyed through nuclear and extranuclear receptors. The traditional notion was that progesterone binds classical progesterone receptors to alter gene transcription. This view has been challenged by the discovery of additional progesterone signaling molecules important for progesterone actions in non-neural cells. In granulosa cells, the progesterone receptor membrane component 1 (Pgrmc1) mediates progesterone effects by forming a receptor complex with binding partner, Serpine mRNA binding protein 1, but it is unknown whether these molecules function similarly in the brain. To begin to address these issues, I investigated the neural role of Pgrmc1 in female mouse brain, rat brain and in neural cells. By examining the neuroanatomical localization, hormonal regulation, and colocalization of Pgrmc1 within key neurons in the neural control of ovulation, Pgrmc1 emerged as a candidate signaling molecule likely to mediate progesterone functions. Furthermore, Pgrmc1 levels regulate the expression of several diverse genes and signaling pathways in neural cells. Taken together, these results demonstrate that Pgrmc1 function is likely to impact diverse neural functions.

Examining the Development of Handedness in Rhesus Monkey and Human Infants Using Behavioral and Kinematic Measures

Nelson, Eliza Lynn — Fri, 03 Dec 2010 11:56:30 PST

Handedness is a widely studied behavioral asymmetry that is commonly measured as a preference for using one hand over the other. Right hand preference in humans occurs at a ratio of 9:1, whereas left hand preference in rhesus monkeys has been estimated at 2:1. Despite differences in the direction and degree of hand preference, this dissertation investigated whether primates share common underlying factors for the development of handedness. Previous work in human infants has identified a predictive relationship between rightward supine head orientation and later right hand preference. Experiment 1 examined the relationship between neonatal head orientation and later hand use in rhesus monkey infants (N=16). A leftward supine head orientation bias was found that corresponded to greater left hand activity for hand-to-face movements while supine; however, neonatal head positioning did not predict later hand use preference for reaching or manipulation on a coordinated bimanual task. A supine posture is common for human infants, but not for rhesus monkey infants, indicating that differences in early posture experience may differentially shape the development of hand use preference. Movement quality is an additional factor that may affect how the hands are used in addition to neonatal experience. 2-D and 3-D kinematic analyses were used to examine the quality of reaching movements in rhesus monkey infants (N=16), human infants (N=73) and human adults (N=12). In rhesus monkey infants, left hand reaches were characterized as ballistic as compared to right hand reaches independent of hand use preference (Experiment 2). Left hand ballistic reaching in rhesus monkeys may be a carryover from earlier primates that relied on very fast reaches to capture insect prey. Unlike monkey infants, reach quality was a function of hand preference in human infants (Experiment 3). By contrast, a right hand advantage for reaching was observed in human adults regardless of left or right hand preference (Experiment 4). Differential hand experience due to hand preference in early infancy may in part be responsible for the hand preference effects on movement quality observed in human infants but not monkey infants. Motor control may become increasingly lateralized to the left hemisphere over human development leading to the right hand advantage for reaching observed in human adults, as well as over primate evolution leading to right hand use preferences in higher primates like chimpanzees. An underlying mechanism such as a right shift factor in humans and a left shift factor in rhesus monkeys may be a common basis for primate handedness. Environmental and experiential factors then differentially shape this mechanism, including species-typical development. Further work examining the ontogeny of hand preference and hemispheric specialization in various primate infants will lead to a greater understanding of how different factors interact in the development of hand use across primate species.

The role of histone acetylation in sexual differentiation of the mouse brain

Murray, Elaine K — Mon, 22 Nov 2010 15:24:14 PST

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.^

Vasopressin Anatomy of the Mouse Brain

Rood, Benjamin D. — Thu, 03 Jun 2010 06:39:59 PDT

The nine amino acid peptide vasopressin acts as a neurohormone in the periphery and a neurotransmitter/neuromodulator in the central nervous system. Historically, research on vasopressin neurons and their projections to the pituitary has helped lay the groundwork for our understanding of peptidergic neurotransmission. Currently, our research on central vasopressin projections is driving a revolution in our understanding of social behavior. Vasopressin affects a number of social behaviors from social memory to aggression to affiliative behavior, such as pair-bonding. Further, with the addition of more and more transgenic mouse models of disease states, anxiety and depression related disorders, and social behavior dysfunction, it is important now more than ever to have a clear knowledge of the mouse vasopressin system, which derives from a number of distinct nuclei within the brain. Here, I map out vasopressin immunoreactivity in the mouse brain, and delineate the subset of brain regions with gonadal steroid hormone-dependent vasopressin immunoreactivity. Such projections are thought to derive from the bed nuclei of the stria terminalis and medial amygdala in the telencephalon. Finally, based on data from mice with lesions of the suprachiasmatic nucleus, I outline the subset of regions that likely receive vasopressin from this source. Our research on the anatomy of the vasopressin system of mice and our attempts to delineate the site of origin of the many vasopressin fibers found throughout the brain suggest that a significant amount of the vasopressin innervation deriving from cells in the bed nuclei of the stria terminalis and medial amygdala project to areas in the midbrain involved in serotonin and dopamine transmission, such as the dorsal raphe and ventral tegmental area. These transmitter systems play a crucial role in the control of anxiety and depression levels as well as motivated behavior and emotional regulation. Our results strongly suggest that a direct link exists between these systems, and future plans include an examination of this possibility. It is our hope that this work will further our understanding of the role of vasopressin and other transmitter systems in the regulation of social behaviors.

Effect of head orientation on dynamic postural stability and torso coordination

Johnson, Molly — Tue, 25 May 2010 11:01:20 PDT

Purpose. Sensory feedback from the vestibular system and neck muscle stretch receptors is critical for the regulation of posture. The relationship of the head to the trunk is a major factor determining the availability and integration of sensory feedback and can be interfered with by varying head orientation. The goal of this research was to assess (1) how adopting different head-on-trunk orientations would impact postural stability, particularly in relation to the stability boundary, during static balance tasks and (2) how adopting different head-on-trunk and head-in-space orientations would impact postural stability, movement characteristics, and multi-segmental torso coordination during a dynamic postural transition task in healthy, young participants.^ Methods. Healthy, young participants were asked to maintain 30 seconds of upright stance and forward lean or to move from sitting to standing with extended, flexed, and neutral head orientations. Dual force plates were used to assess postural stability from center of pressure variability, range, velocity, or time-to-contact. Six motion capture cameras were used to assess kinematics. During the sit-to-stand task, head velocities, trunk flexion, and movement phase durations were calculated. Segment cross-correlation and joint range of motion were calculated for six torso segments.^ Results. Extended head-on-trunk orientations decreased postural stability during upright stance, forward lean, and the sit-to-stand movement compared to flexed or neutral orientations. During the sit-to-stand task, head-on-trunk extension, with or without head-in-space extension, led to reduced head velocities, trunk flexion, movement duration, and transition phase duration. Head extension led to increased inter-segmental torso motion, and decreased temporal coordination of torso segments.^ Conclusions. This study demonstrated that interfering with head-trunk posture by adopting head extended orientations impairs balance and leads to sit-to-stand strategy changes that may interfere with movement and coordination. Results show that head-on-trunk extension is more critical than head-in-space extension for determining postural and movement changes. The findings suggest that vestibular system interference may not be the main route through which head extension impacts postural control, but that extensor muscle stretch receptors may be a factor in the posture and movement changes associated with head-on-trunk extension. It is possible tonic neck muscle activity is a critical factor for regulating balance and movement.^

Effects of Sex and Social Status on Neuromuscular Differentiation in the Eusocial Naked Mole-Rat (Heterocephalus Glaber)

Seney, Marianne Louise — Fri, 04 Dec 2009 08:49:23 PST

Naked mole-rats live in large colonies and exhibit a strict reproductive hierarchy. Each colony has 1 breeding female and 1-3 breeding males; all other individuals are non-reproductive subordinates. Subordinates show a remarkable lack of sex differences in behavior and anatomy, but can become reproductive if removed from the colony. The striated perineal muscles and their innervating motoneurons, which are sexually dimorphic in all other mammals examined, are not dimorphic in subordinate naked mole-rats. Here I asked whether sexual differentiation of this neuromuscular system occurs when subordinates become breeders. Sex differences in perineal motoneurons were not observed, regardless of social status. To my surprise counts of motoneurons in Onuf’s nucleus were increased in breeders of both sexes. This was accompanied by a reciprocal decrease in cells in Onuf’s nucleus that were characterized by small soma size. The neuronal changes correlate with increased perineal muscle volumes in breeders. Although not exhibiting typical motoneuron morphology, some small cells fit a neurochemical or functional definition of a motoneuron. I propose that small cells are recruited to the pool of large Onuf’s nucleus motoneurons when subordinate naked mole-rats become breeders. I then looked at naked mole-rats of varying status (subordinates, paired animals that have never reproduced, intact breeders, and gonadectomized breeders) to determine which cues elicit changes in perineal muscles and small cells in Onuf’s nucleus. I found that pairing is sufficient to cause decreases in the population of small cells in Onuf’s nucleus, while production of litters is necessary for increasing in perineal muscle size. The gonads were not necessary to maintain changes in small cells or perineal muscles. I hypothesized that the lack of sex differences in naked mole-rats might be related to their unusual social structure. To test this, I compared the genitalia and perineal muscles in three African mole-rat species: the naked mole-rat, the solitary silvery mole-rat, and the Damaraland mole-rat, a species considered to be eusocial, but with less reproductive skew than naked mole-rats. My findings support a relationship between social structure, mating system, and sexual differentiation.