published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

Direct fitness is measured as the number of surviving offspring. Thus adult males may try to produce as many offspring as possible or to increase the survival of their offspring. Recent findings have shown the many potential benefits of fathers’ presence and support on infants’ development and survival. However, little is known about the influence of socio-ecological factors on male-infant interactions. The main aim of this thesis was therefore to investigate male-infant interactions in wild crested macaques (Macaca nigra). In particular, we aimed to examine the affiliative and agonistic interactions taking place in this species, along with the factors influencing these interactions and offspring survival. Data collection for this thesis took place in the Tangkoko-Duasudara Reserve in Sulawesi, Indonesia, on 3 wild groups of crested macaques. For the first study, data were collected on migrations, births, disappearances, and encounters between groups over 5 years. We analyzed the influence of socio-ecological factors (e.g. rainfall, alpha-male position takeover, and male hierarchy stability) on pre- and post-natal loss. The results showed that high infant mortality was mainly associated to male alpha-position takeover, which suggests that infanticide may indeed occur in this species. In addition, we found that female within-group competition for food sources and between-group resource defense influenced fetal and infant loss. Based on these findings, we were interested to see whether fathers protected their own offspring against male attacks. Thus, in the second study, we investigated the social determinants and characteristics of male-infant affiliations. Our results indicate that adult males and infants form preferential association, and that infants initiate the majority of male-infant affiliations. Infants initiated affiliations mainly towards a high ranking male or a male in a close relationship with their mother. In addition, infants affiliated mainly with adult males in the absence of their mother, while males affiliated mostly with infants when the infants‘ mother was present in proximity. Furthermore, males initiated affiliations towards an infant when they held a high rank or when they had a strong bond with the infant‘s mother. Interestingly, paternity did not affect male-infant affiliations. In conclusion, these studies provide insights in the specifics of both infant survival strategies and male reproductive strategies. In addition, we show that infants are active agents in establishing and maintaining preferential relationships with males. This thesis, thus, confirm that male-infant interactions, although rare, have a strong influence both on males’ and infants’ direct fitness.

Mirror image stimulation (MIS) is reported to elicit persistent social responses in monkeys, in contrast to most humans and great apes, who exhibit self-recognition. The abnormal features of a mirror image as a social stimulus have generally been ignored in monkey reports, whereas research with other animals has identified some important differences between MIS and other stimuli. Differential agitation during separations in peer-reared and mirror-reared infant stumptail monkeys suggests that even the limited opportunity for physical contact with a reflection renders it a sub- optimal attachment-eliciting stimulus. Mirror-rearing appeared to only slightly diminish responsiveness to pictures of conspecifics, compared to peer-rearing. Animals reared with no form of social stimulation exhibited less responsiveness to pictorial stimuli, and engaged in more abnormal and self-directed behaviours than mirror- or peer-reared animals, indicating that a mirror can at least partly compensate for the absence of a true social companion during rearing. The extent of abnormal behaviours in alone-reared stumptail monkeys appears to be considerably less than that reported in rhesus monkeys. The mirror was reacted to as a social partner by mirror-reared animals, and correlations between behaviours, and between measures of a single behaviour, were similar in mirror- and peer-reared groups. However, a live cagemate received 50% more social behaviour than did a reflection, with play behaviours producing group differences in rate, duration, bout length, and variability. MIS or a peer behind Perspex reduced separation agitation in pair-reared but not group-reared infants. In comparison to a peer behind Perspex, MIS received positive responses in mirror-reared and pair-reared animals, whereas group-reared animals reacted more ambivalently to the abnormal animal represented in the mirror. Those mirror-reared animals who received additional experience of a peer behind Perspex during rearing reduced responding to the mirror, whereas responsiveness in mirror-only-reared animals persisted. Peer-only-reared animals were also highly responsive to MIS, possibly due to novelty. Alone-reared subjects, when tested in a familiar setting, were the most responsive of all the subjects to MIS. None of the subjects exhibited self-recognition, even although some had approximately 3,500 hours of experience of a triple mirror image effect, and an additional six months group mirror experience. Some results were obtained with small numbers of subjects, so caution is required in interpretation.

B virus (Macacine herpesvirus 1), subfamily Alphaherpesvirinae, causes a fatal, neurovirulent infection in zoonotically infected humans. Macaques (Macaca sp.) serve as the natural host for B virus and they are frequently seropositive for B virus antibodies without showing any overt signs of disease. The global hypothesis of these studies is that B virus, a highly cytopathic virus in macaques, subverts the innate immune responses in the host (macaques) that has co-evolved with it (the virus) differently than it does the foreign host (humans). The foreign host, frequently fails to produce neutralizing antibodies early after infection and this may be due to a dysregulation or inhibition of pathways known to play a role in the innate immune response which directs the adaptive defense responses. Current knowledge is that at least five major signaling pathways can be activated after a pathogen such as B virus enters a host cell (REF). These include the IRF3 pathway, the NFkB pathway, the NFAT pathway, and the MAPK pathway. Early stimulation of one or more of these pathways leads to the induction of the proinflammatory response and subsequent induction of cytokines such as IL6, IL8 and IL10, and apoptosis. Cytokine induction and apoptosis play important roles in host-pathogen interactions, innate defense induction and subsequent adaptive immune responses. Using a primary cell model that is representative of the first target cells of B virus in the natural and foreign host, we investigated one of the key signaling pathways, the MAPK pathway, induced by B virus early after infection (Farah-Abraham and Hilliard, unpublished data). My data suggest that macaque and human cells differ in the induction kinetics of MAPK (JNK and p38) activation. These data reveal differences between foreign and natural host cells in how each controls apoptosis, and demonstrate that inhibition of p38 activation reduced and with high dose inhibition terminated B virus replication in human cells, and played a role in reduction of apoptosis-associated mediators. The importance of each component in the MAPK pathway is investigated with respect to virus replication in macaque and human cells that represent the primary target cells in acute infection. Knowledge of these events provides an understanding of how the innate immune responses can be modulated by B virus to shape the adaptive immune response to limit how the virus replicates and spreads. Further, these data may provide insight into a novel target for the design of new antivirals to inhibit this deadly zoonotic virus. This research will help us understand how the early molecular mechanisms of host-pathogen interactions result in modulation of the innate immune responses and how certain aspects of a normally defensive (protective) host response can be re-directed or modified depending on the nature of the virus:host relationship.

No description available.

Thesis (Ph. D.)--Ludwig-Maximilians-Universität München, 2000. / Title from PDF t.p. (viewed on June 4, 2006). Includes bibliographical references (p. 65-76).

PURPOSE: To characterize the distribution of white matter neurons (WMNs) positive for perineuronal nets (PNNs) in the adult monkey. WMNs are a mixed population of excitatory and inhibitory neurons. They have an important role in axon guidance during cortical development, but their role in the adult brain is less understood. In vitro and in vivo experiments provide evidence that WMNs are incorporated into cortical circuitry. The majority of investigations in the adult, however, have focused on regional variations in overall density, or on characterization of morphological and neurochemical subtypes. The present study was motivated by the observation that some WMNs exhibit PNNs in adult monkey. Since PNNs are associated with plasticity in younger animals, their occurrence with some WMNs might be functionally significant. METHODS: PNNs were visualized, at the light microscopic level, by WFA staining in three adult macaque brains. Density of WFA positive WMNs was scored at three anterior-posterior levels (frontal, mid-hemispheric, and occipital), and compared with overall density of WMNs, as visualized by immunocytochemistry for NeuN. Quantitation of WFA+ neurons and neuron morphology were analyzed via light microscopy. Soma size and appearance, and dendritic length were recorded and measured. RESULTS: On the basis of soma size and proximal dendritic shape, several types of WFA+ WMNs were provisionally identified, consistent with previous reports in the literature. Subpopulation densities were of highest density in mid-cortical areas and lowest quantities at occipital, matching previous studies. Morphological measurements suggested a heterogeneous neuron population through soma measurements and dendrite orientation. Soma sizes exhibited a range of circularity and size (10 µm – 30 µm). Dendrites were stained beyond the “proximal” area, including intermediate areas beyond the first branch, and up to 500 µm. CONCLUSIONS: A small population of WMNs are coated by PNNs in adult monkey. On the basis of morphology, these might be further subdivided, but combined studies with other markers would be needed. Future studies might investigate age- or pathology-related changes in the density and subtypes of WMNs that express PNNs in human or nonhuman primates. We speculate that these WMNs might have functional specializations, perhaps similar to the plasticity effects documented for PNNs in early development.

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第22229号 / 理博第4543号 / 新制||理||1653(附属図書館) / 京都大学大学院理学研究科生物科学専攻 / (主査)教授 濱田 穣, 准教授 平﨑 鋭矢, 教授 髙井 正成 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

archives@tulane.edu / Background: Human Immunodeficiency Virus-1 (HIV-1) has killed over 35 million and infects 1.8 million new people each year. Antiretroviral therapy (ART), although effective controlling plasma viremia and transmission, does not purge latent or persistent reservoirs necessary to eliminate infection, and must be maintained for life. It is thus imperative to discover therapeutics that provide both lifetime suppression of viral loads and depletion of viral reservoirs. Methods: To harness the immunosurveillance capacity of highly functional and persistent CMV-specific adaptive response, rhesus PBMCs were stimulated with rhCMV peptide pools (IE1, IE2, and pp65) to expand rhCMV-specific T cells. These cells were then genetically modified with retroviral vectors expressing a CD4 extracellular domain linked to T cell intracellular signaling domains that instruct CTL activity, converting them into HIV-specific effector cells. Vectors combine CD4 targeting with an maC46 fusion inhibitor to protect against viral entry. In a reversal of the critical step in the HIV viral lifecycle whereby virus targets new CD4+ host cells using its Env glycoprotein, these genetic modifications redirect host immune responses to target and kill Env expressing infected cells. We hypothesize that continuous stimulation of CD4-CAR T cells through their rhCMV-specific TCR will maintain activated T effector memory CTL capable of targeting HIV infected cells. Results: We find that autologous rhPBMCs can be expanded ex vivo with rhCMV peptides up to therapeutically relevant numbers for adoptive transfer. This rhCMV-specific T cell expansion enriches cells in a phenotype consistent with T effector memory differentiation. Following genetic modification and adoptive transfer, cells reach peak expansion at seven days post infusion into ART suppressed or unsuppressed SHIV infected Rhesus Macaques. We observe these cells capable of persisting in vivo for at least 2 years following reinfusion. Furthermore, these cells are maintained in vivo in an effector memory phenotype throughout the duration they were analyzed. Despite this, SHIV plasma viral loads remain unchanged. Conclusion: These studies establish use of rhCMV-specific T cells as an effective way to produce persistent genetically modified cells targeting SHIV. Future studies will need to further increase in vivo expansion, protection, and CTL activity as viral loads remain detectable. / 1 / Nathan Michel Johnson

Human and non-human primates (NHP) undergo age-related cognitive decline beginning as early as middle-age, even in the absence of an underlying pathology or disease. Growing evidence indicates that an increase in white mater pathology related to rising chronic levels of inflammation may be key contributors to age related cognitive decline. Curcumin (CUR), the active ingredient in turmeric, is a polyphenol nutraceutical with potent anti-inflammatory and antioxidative effects. Several ongoing research studies are underway to explore this potential anti-aging compound. For the first time in a rhesus monkey model of aging, we studied the effects of CUR supplementation on cognition and inflammation. Baseline MRI, blood, CSF and cognitive data were collected for all monkeys. Monkeys were fed daily doses of 500mg of CUR or a vehicle control over 18-months during which three rounds of a battery of cognitive testing was performed along with regular collection of blood, CSF and MRI. Following completion of this testing and specific to this thesis, monkeys were further tested on object discrimination, object and spatial reversal tasks. No significant differences were observed between groups in object discrimination task performance. CUR treatment improved performance on object reversal testing, with treated monkeys making fewer perseverative type errors. At the completion of behavioral testing, serum samples from two-year post treatment onset and brain tissue were harvested for post-mortem analysis of markers of inflammation. The density and morphology of microglia, the resident immune cells of the brain, were examined using immunohistochemistry on serial coronal sections through frontal cortical gray (A46, A25) and while matter (FWM, CC, and CngB) regions that are implicated in cognitive aging. We demonstrated that CUR treatment did not significantly alter the density of presumably immune-activated microglia expressing the MHC class II marker LN3. However, treatment did affect morphological features of microglia specifically within the while matter. Within the white matter, CUR treatment was associated with a significant increase in microglial ramification, evidenced by greater process length, number of nodes and convex-hull area and volume. Increased microglial ramification suggests greater likelihood of microglial surveillance within the white matter associated with CUR treatment. No significant group differences however were observed in the select serum cytokine levels quantified using multiplex ELISA, or in inflammatory gene expression in brain tissue measured with qRT-PCR. While our findings show the benefit of CUR supplementation on cognitive performance and its effects on microglial morphology, further study is needed to understand the precise changes that CUR supplementation may have on inflammation.