An organism’s spatial ecology allows for access to essential resources such as food, mates, and escape from predators. Home range size, or the total area an organism inhabits, varies in relation to numerous factors including seasonality. During the breeding season, home range size increases in males across taxa. In addition, males usually also have larger home range sizes than females. This implicates testosterone (T) as a possible mediator of this relationship. Indeed, T causes an increase in home range size of males in numerous species of lizards. In addition to T causing an increase in home range size, it also causes an increase in coloration, which is used as a signal to deter or elicit aggressive behaviors in lizards. Potentially, contests are less common in natural settings than in the lab due to this signaling despite increased frequency overlap of home ranges in males. The larger the home range size of males, mediated through an increase in T, the more overlap with conspecifics. With this increase in spatial demand, or home range size, there is often a corresponding increase in spatially related brain regions. In reptiles, these brain regions are the medial and dorsal cortices (MC and DC respectively). The increase in cortical brain region size due to an increase in spatial demand may be mediated by an increase in neurogenesis. Proliferation of neurons occurs along the ventricles and radiate to numerous regions in the brain including the MC. With respect to the MC, immature neurons, which express the protein doublecortin (DCX), migrate from the ventricles, through the inner plexiform layer and are integrated into the cell layer. Because DCX is only expressed in recently born, migrating neurons, it can be used to measure neurogenesis. In mammals and birds, neurogenesis and growth of certain brain regions is affected by steroid hormones, including T. Here we tested two hypotheses: (1) T affects the home range size of Sceloporus occidentalis and (2) cortical brain region volumes are related to home range size and/or T which is mediated through changes in rates of neurogenesis. We surgically castrated individuals and implanted subjects with either a T-filled implant or blank implant and then released them at their initial capture sites. In addition to these castrated individuals, subjects not subjected to castration served as unmanipulated controls. Home range size of individuals in the field was quantified using a global positioning system (GPS) unit and later delineating those GPS points using minimum convex polygons (MCPs). We predicted that (1) castrated, T-treated lizards and unmanipulated control lizards would have larger home range sizes than castrated, control lizards c and (2) MC and DC cortices would be larger in volume and contain more DCX-immunoreactive cells in the lizards with the highest circulating T levels and with the largest home range sizes. We found that increased T caused an increase in the number of blue abdominal scales. We found no differences in home range size relating to T. Likewise, T did not affect MC volumes. However, we did observe a decrease in DC volume with increasing plasma levels of T. Because T did not affect home range size, it follows that we did not find an effect of T on MC volume. However, the significant result of T causing a decrease in DC volume implies a possible trade off with regards to energetics and the maintenance of brain region volumes as prior research indicates that T in increases energy expenditure and decreases foraging efforts.

Reptiles exhibit neurogenesis throughout the brain during adulthood. However, very few studies have quantified telencephalon-wide neurogenesis in adulthood, and no studies have performed these investigations in snakes. Quantifying neurogenesis in the adult snake is essential to understanding class-wide adult neurogenesis and providing insight into the evolution of this trait. The thymidine analog 5-bromo-2’-deoxyuridine (BrdU) was used to quantify cell proliferation, migration, and survival in the ball python (Python regius). First, to determine the proper dose of BrdU for injection we subcutaneously injected 50mg/kg, 100mg/kg, and 250mg/kg into 15 adult male P. regius. We found the 250mg/kg dose marked significantly more cells than the 50mg/kg dose, but not the 100mg/kg dose. Then we subcutaneously injected 100mg/kg BrdU into 15 juvenile male P. regius at 3 different time points (2 days, 2 weeks, 2 months) prior to sacrifice to quantify proliferation, migration, and survival of cells in several telencephalic subregions. After sectioning and immunohistochemical staining, we found proliferation to be highest in the accessory olfactory bulb (AoB), retrobulbar regions (AD, AV), dorsal ventricular ridge (DVR), and dorsolateral amygdala/lateral amygdala (DLA/LA). Of the proliferating cells, the proportions of cells that migrated after 2 weeks were highest in the ventral lateral region (VL), anterior medial and lateral cortices (aMC, aLC), and anterior NS (aNS). After 2 months, the highest proportional survival was in the AoB, aLC, aMC, aNS, DVR, and ventral medial regions (VM). Regions involved in long-term functions like spatial memory may require less proliferation and longer survival, while regions involved in short-term functions undergo more proliferation with higher relative attrition.

The hippocampus is a brain region that can undergo tremendous plasticity in adulthood. The hippocampus is related to the formation of spatial memories in birds and mammals. In birds, plasticity in the hippocampus occurs when formation of such memories is directly relevant to survival or reproduction, such as for breeding or food caching. In reptiles, the homologues to the hippocampus are the dorsal and medial cortices (DC and MC). In several lizard, snake and turtle species, these structures have been related to spatial memory. Experimental investigations indicate that differences in DC volume are related to space use associated with differing foraging ecologies. Differences in MC volume have been associated with territory size-based mate acquisition strategies. Furthermore, territory size has previously been correlated with plasma testosterone (T) levels. Therefore, I hypothesized that neuroplasticity within the MC/DC is controlled by demands on spatial navigation and seasonal differences and that these changes may involve the action of T. During two experimental trials, male Western Fence Lizards (Sceloporus occidentalis) were placed into either large or small semi-natural enclosures and allowed to interact with a female and intruder males over the span of seven weeks. One trial was performed during the spring breeding season and the other during the summer non breeding season, to examine seasonal differences in plasticity. Blood samples were collected at initial time of capture and before sacrifice to measure plasma T. Immunostaining for doublecortin was used to determine the density of immature neurons in each region, and cresyl violet staining allowed for volume measurements of specific regions. MC cell layer neurogenesis was higher in lizards placed in large enclosures than those in small enclosures and higher in the summer than in the spring. DC volume was smaller in lizards held in large enclosures than those in small enclosures. The decreased DC volume seen lizards held in large enclosures may indicate a cost to the increased neurogenesis in the MC of lizards in the same enclosures. These results indicate a possible trade-off between DC volume and MC neurogenesis that allows for switching between the ability to solve novel spatial tasks using the DC while storing a cognitive map in the MC. During the spring, T had no relationship with MC volume, while during the summer this was negative, so effects of T on the MC may be seasonal.

Thesis (Ph.D.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / The vagina is a key organ in the peripheral genital arousal response. In animal models, pelvic nerve stimulation increases vaginal wall compliance, blood flow and transudation of fluid. Decreases in ovarian steroids are known to induce structural changes in the vagina, and evidence is mounting that alterations in the hormonal milieu contribute to genital pathophysiology. To date, however, mechanisms by which sex steroids regulate vaginal arousal responses have not been adequately studied. Further, limited data are available on the effects of hormone replacement on tissue morphology, hormone receptor distribution and vaginal innervation. We propose that imbalances in sex steroid hormone levels alter the distribution, expression and actions of steroid receptors and neurotransmitters, leading to structural and functional changes in vaginal tissue and impairment the arousal response. The goal of this study was to assess dynamic changes in vaginal tissue structure with hormone deprivation and administration. Female Sprague-Dawley rats were used as an animal model. Intact animals served as controls. Ovariectomized animals were treated for a two week period with vehicle, estradiol, testosterone, progesterone, or a combination of estradiol plus testosterone or progesterone. To assess changes in vaginal physiology and morphology, physiological and histological techniques were used, including stereological analysis and immunohistochemistry for localization of hormone receptors and various neuronal markers. / 2031-01-01

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.

High doses of 3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy") are known to reduce levels of various serotonergic markers outside of the raphe nuclei. To test the hypothesis that these deficits reflect a degeneration of distal axons/terminals, we investigated the effects of an MDMA binge (10mg/kg x 4) on the relative protein and genetic expression of several serotonergic markers in rats, as well as the effects of this compound on the quantity of serotonergic terminals in these animals. In experiment I, we examined whether MDMA alters serotonin transporter (SERT) levels as determined by lysate binding and immunoblotting analyses. Both methods of analysis revealed MDMA-induced reductions in regional SERT content. Experiment II investigated MDMA-induced changes in terminal-specific levels of SERT and the vesicular monoamine transporter 2 (VMAT-2) in the hippocampus, a region with sparse dopaminergic innervation, after lesioning noradrenergic input with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). Animals were administered 100 mg/kg DSP-4 or saline 1 week prior to MDMA (or saline). As determined by immunoblotting of synaptosomal tissue, the DSP-4/MDMA group showed little change in hippocampal VMAT-2 protein expression compared to DSP-4/Saline controls, despite large reductions in SERT levels in all regions examined in the MDMA-treated animals. Experiment III examined whether MDMA alters genetic expression of SERT and VMAT-2. When compared to saline-treated controls, animals given MDMA showed a striking decrease in SERT gene expression (and a lesser effect on VMAT-2) in dorsal/median raphe as assessed by quantitative RT-PCR. Experiment IV(a) investigated the effects of MDMA on gene and protein expression of tryptophan hydroxylase (TPH) in the hippocampus. Levels of TPH protein were unchanged between treatment groups, while transcript levels were decreased 15-fold in the dorsal/median raphe. In experiment IV(b), flow cytometry was used to measure whether MDMA alters the quantity of serotonergic terminals in the hippocampus. MDMA-treated animals showed an increase in the number of serotonergic synaptosomes identified by co-labeling for synaptosome-associated protein of 25 kDa (SNAP-25) and TPH. These results demonstrate that MDMA causes substantial regulatory changes in the expression of serotonergic markers with no evidence for synaptic loss, questioning the need to invoke distal axotomy as an explanation of MDMA-related serotonergic deficits.

Propionic acid (PPA) is a short chain fatty acid that is produced by the human gut microbiome. Propionate, butyrate and acetates are the end products of the fermentation of the complex carbohydrates by human gut friendly microbiome and are being used as sources of energy in our body. PPA is used as a food preservative against molds in various daily products and has been implicated in the pathogenesis of autism. In a recent study we showed that PPA in human neuronal stem cell (NSC) culture increases the astrocyte population and decreases the neuronal number and increases the inflammatory cytokines. In this study, we investigated the potential effects of a propionic acid-derivative, Ibuprofen, a member of the non-steroidal anti-inflammatory drugs (NSAIDs) on neural stem cells proliferation and differentiation in vitro. Ibuprofen is an over counter drug that is used for alleviating pain, headache, and fever. To examine the effect of ibuprofen on developing brain we used human NSC in vitro, exposed them to increasing concentrations of ibuprofen, and investigated neural proliferation and differentiation. Here we show that NSAIDs, not at therapeutic, but very high concentrations cause an imbalance in NSC differentiation towards glial cells, therefore causing astrogliosis seen in some cases of autism spectrum disorder (ASD). Furthermore, upon removal of Ibuprofen, inflammatory cytokines; TNF-alpha, IL-6 and IL-10, significantly increase (p < 0.05) in cells previously exposed to NSAIDs compared to control. Therefore, we are speculating that if such drugs were to be taken in the circumstances of a developing child during the early trimesters of pregnancy, this could result in increased glial:neuron ratio leading to lifelong impediments. Based on the current study our recommendation is to avoid high doses of propionic acid derivatives such as ibuprofen during pregnancy.

One of the most prevalent diseases acquired in older populations and currently the most common form of dementia, exists in the form of Alzheimer's [1]. Progressing over time, Alzheimer's begins intramolecularly through the buildup of amyloid precursor protein derived Aβ peptides which aggregate into neurotoxic fibrils. The fibrils result in damage to memory and cognitive systems, leading to depression of routine function and eventual death. There is currently no cure nor treatment by which this plaque buildup can be prevented or eliminated, and as such, significant work is being made towards this topic. It has been recently discovered that the human matriptase protein is capable of cleaving both the amyloid precursor protein from which Aβ peptides are made as well as the Aβ1-42 peptide itself, facilitating interest into its potential to reduce fibril formation [2][3]. In this study we set out to determine if the human matriptase serine protease domain can cleave Aβ fibrils or prevent the Aβ fibril formation in vitro. A recombinant matriptase serine protease domain (r-MatPD) was subcloned into a pET-28a-c(+) expressing vector, expressed, and purified via Ni-NTA affinity resin. The purified his-tagged r-MatPD was further auto-activated and incubated with the purified recombinant Aβ1-42 peptides. We observed that r-MatPD can cut polymerized Aβ1-42 into smaller fragments and prevent Aβ1-42 fibril formation. Effectively, this study suggested that the matriptase protease domain can be further investigated for its role in Aβ fibril clearance in vivo with a possibility of developing matriptase therapeutic potentials in treating Alzheimer's patients.

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