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.

Thesis (Ph.D.)--University of the Witwatersrand, Faculty of Science, 2000.

The naked mole-rat (Heterocephalus glaber) demonstrates a strict social and reproductive hierarchy. Oxytocin (OXT) is a peptide hormone that acts both peripherally and centrally in the regulation of a number of sexual and social behaviours. The main area of central production of this peptide is the paraventricular nucleus of the hypothalamus (PVN). The present study characterized differences that exist in OXT neurons in this region. Breeders and subordinates from established colonies were sacrificed and brains were processed for OXT-immunoreactivity. Four further groups of paired animals underwent various social and hormonal manipulations (opposite-sex paired, same sex-paired, opposite-sex/gonadectomised paired, opposite-sex/vasectomized paired) and were also used for analysis. Results showed that subordinate naked mole-rats had significantly more OXT-immunoreactive neurons in the PVN than either breeders or paired animals that had been gonadectomised. However, no differences were found on measures of OXT cell volume. Possible functional significance of these differences is discussed.

The naked mole-rat (Heterocephalus glaber) demonstrates a strict social and reproductive hierarchy. Oxytocin (OXT) is a peptide hormone that acts both peripherally and centrally in the regulation of a number of sexual and social behaviours. The main area of central production of this peptide is the paraventricular nucleus of the hypothalamus (PVN). The present study characterized differences that exist in OXT neurons in this region. Breeders and subordinates from established colonies were sacrificed and brains were processed for OXT-immunoreactivity. Four further groups of paired animals underwent various social and hormonal manipulations (opposite-sex paired, same sex-paired, opposite-sex/gonadectomised paired, opposite-sex/vasectomized paired) and were also used for analysis. Results showed that subordinate naked mole-rats had significantly more OXT-immunoreactive neurons in the PVN than either breeders or paired animals that had been gonadectomised. However, no differences were found on measures of OXT cell volume. Possible functional significance of these differences is discussed.

Having an appropriate understanding of the behavioral and physiological impact of a disease requires thoroughly fielded tests and wide-ranging animal models to properly deduce generalized impacts of the disease under investigation. Through novel animal models, we acquire diverse insights into the mechanisms at play so that we may approach the problem at hand with fresh perspective and renewed vigor. Using the naked mole-rat (Heterocephalus glaber), a species becoming increasingly common in the medical sciences, my dissertation aimed to accomplish the aforementioned goals in two parts: 1) take the naked mole-rat through a battery of behavioral tasks to bolster our capabilities of using this animal model in medical research; and 2) introduce the naked mole-rat as an alternative model for the investigation of how loss of dental sensation alters behavior and neuroanatomy. Chapter two describes the many methods with which I tested the naked mole-rat across a variety of typical behavioral tasks for social dominance, learning and memory, anxiety, depression, and sociability. Included herein were tests to determine appropriate motivators for this subterranean species to perform such tasks. Additionally, due to the naked mole-rat’s unique disposition for biting, I measured their biting behaviors and compared them across rodent and other mammalian species. The results show that naked mole-rats exhibit large evolutionary divergence in their sensory capabilities and great consideration needs to be given to the proper behavioral tasks and subsequent evaluations of these behavioral paradigms. In chapter three, I evaluated the impact of tooth extraction on affective behaviors, learning and memory, and sociability. Chapter four sought to uncover underlying neuroplasticity associated with the behavioral tasks performed in chapter three. Additionally, in chapter four, I investigated plasticity of the traditional somatosensory pathway for tooth sensation. Tooth loss decreased neuronal density of contralateral ventral posteromedial nucleus of the thalamus and increased the neuronal density of the contralateral ventral dentate gyrus, indicating that tooth-loss induced neuronal plasticity may be more related to plasticity of pain circuitry or resultant from alterations in the muscles of mastication following tooth loss. Though no significant changes in the hippocampus arose from one year of living with no right incisor, I theorized as to which of the physiological idiosyncrasies exhibited by Heterocephalus glaber may have inhibited any observable plasticity due to tooth loss.

Background: A variety of microbial communities exist throughout the human and animal body. Genetics, environmental factors and long-term dietary habit contribute to shaping the composition of the gut microbiota. For this reason the study of the gut microbiota of a mammal exhibiting an extraordinary life span is of great importance. The naked mole-rat (Heterocephalus glaber) is a eusocial mammal known for its longevity and cancer resistance. Methods: Here we analyzed its gut microbiota by cultivating the bacteria under aerobic and anaerobic conditions and identifying their species by mass spectrometry. Results: Altogether, 29 species of microbes were identified, predominantly belonging to Firmicutes, and Bacteroidetes. The most frequent species were Bacillus megaterium (45.2 %), followed by Bacteroides thetaiotaomicron (19.4 %), Bacteroides ovatus, Staphylococcus sciuri and Paenibacillus spp., each with a frequency of 16.1 %. Conclusion: Overall, the gut of the naked mole-rat is colonized by diverse, but low numbers of cultivable microbes compared with humans and mice. The primary food plants of the rodents are rich in polyphenols and related compounds, possessing anti-microbial, anti-inflammatory, anti-oxidative as well as anti-cancer activity which may contribute to their exceptionally healthy life.

Background: The naked mole-rat (NMR) is a long-lived and cancer resistant species. Identification of potential anti-cancer and age related mechanisms is of great interest and makes this species eminent to investigate anti-cancer strategies and understand aging mechanisms. Since it is known that the NMR expresses higher liver mRNA-levels of alpha 2-macroglobulin than mice, nothing is known about its structure, functionality or expression level in the NMR compared to the human A2M. Results: Here we show a comprehensive analysis of NMR- and human plasma-A2M, showing a different prediction in glycosylation of NMR-A2M, which results in a higher molecular weight compared to human A2M. Additionally, we found a higher concentration of A2M (8.3±0.44 mg/mL vs. and 4.4±0.20 mg/mL) and a lower total plasma protein content (38.7±1.79 mg/mL vs. 61.7±3.20 mg/mL) in NMR compared to human. NMR-A2M can be transformed by methylamine and trypsin resulting in a conformational change similar to human A2M. NMRA2M is detectable by a polyclonal antibody against human A2M. Determination of tryptic and anti-tryptic activity of NMR and human plasma revealed a higher anti-tryptic activity of the NMR plasma. On the other hand, less proteolytic activity was found in NMR plasma compared to human plasma.

The naked mole-rat (Heterocephalus glaber) is one of the most social mammals on the planet. These animals live in underground colonies consisting of a breeding female (the “queen”), 1 to 3 breeding males and up to 300 nonreproductive “workers” organized in a dominance hierarchy. In addition to their eusociality, naked mole-rats have evolved many extreme biological characteristics including an exquisite sense of touch and insensitivity to certain types of pain. However, the overlap between the social and somatosensory abilities of naked mole-rats remains mysterious. In this work, we show that naked mole-rats exhibit caste-like behavioral signatures linked to eusociality, predominantly utilize snout-to-snout interactions in social behavior and possess a somatosensory profile to mechanical stimuli distinct from mice. In the first chapter of this work, we leveraged machine learning and molecular biology tools to create a behavioral atlas of naked mole-rat behavior. We first utilized a computational pipeline of pose-tracking using SLEAP and behavioral segmentation using keypoint-MoSeq to identify 20+ behavioral syllables. This showed that the queen naked mole-rat has a distinct behavioral phenotype from the workers, consisting of faster movements, less anxiety-like freezing, and less colony maintenance behaviors such as digging. We next showed that behavioral differences exist between the workers and that the dominance rank of a given individual could be predicted by its spontaneous behaviors in an open field. Relative rank differential appeared to have relevance for social behaviors: during a tube test for dominance, pairings of a high-ranked and low-ranked animal occurred more quickly and were won more frequently by the dominant animal. Snout touch played an integral role in these dominance tests (perhaps in the communication of individual ID information). This prompted us to investigate snout-to-snout interactions in the open field. We found that two familiar naked mole-rats from the same colony engaged in hundreds of snout interactions in a 10-minute period, and the number of interactions was nearly twice as high between two foreign animals. Follow-up experiments explored the molecular basis of this snout touch and showed that mechanosensory channels (e.g. Piezo2) are likely involved in social snout-to-snout interactions. Furthermore, trimming the sensory whiskers of naked mole-rats disrupts their ability to recognize conspecifics and alters their relative dominance relationships. These findings uncover face touch as a prominent social behavior in naked mole-rats that is intimately linked to social recognition. In the second chapter of this work, we more deeply investigated naked mole-rat somatosensation by using high-speed videography. We began by determining how naked mole-rats respond to both innocuous stimuli (cotton swab, dynamic brush) and noxious stimuli (light and heavy pinpricks) when given to the hindpaw. Compared to mice, naked mole-rats showed a distinct hindpaw phenotype, never responding to innocuous touch stimuli, responding to light pinprick, but rarely responding to heavy pinprick (normally the most noxious stimulus that elicits the strongest pain response in mice). Interestingly, naked mole-rats do respond to brush stimuli to the back skin with a dorsiflexion posture. These animals also exhibit an idiosyncratic withdrawal response to a brush applied to the snout skin which appears to be highly aversive. Interestingly, the velocity of this aversive snout withdrawal appears to be socially modulated and is decreased in the presence of another naked mole-rat in the testing chamber. This phenotype does not occur in mice and provides additional evidence that the naked mole-rat snout is not only extremely sensitive but plays a role in processing socially relevant information.

Naked mole-rats are eusocial rodents that live in subterranean colonies with a strict reproductive and social hierarchy. Breeders are socially dominant and other colony members are non-reproductive subordinates. The effects of manipulating the serotonergic system on aggression are well studied in many species, but not in eusocial rodents like the naked mole-rat. For the current study, the effects of fluoxetine hydrochloride (FLX) on status-specific behaviours of subordinates (Experiment 1) and queens (Experiment 2) were evaluated both in-colony and in a social-pairing paradigm to investigate how the serotonergic system influences aggression in this species. In accordance with our main hypothesis, chronic treatment of FLX attenuated the frequency and duration of aggression in queens, but not subordinates, when paired with an unfamiliar conspecific. Further exploration of pharmacological manipulation on status-specific behaviours of this eusocial species may elucidate the neurobiological mechanisms underlying their unique and rigid social hierarchy.

Naked mole-rats are eusocial rodents that live in subterranean colonies with a strict reproductive and social hierarchy. Breeders are socially dominant and other colony members are non-reproductive subordinates. The effects of manipulating the serotonergic system on aggression are well studied in many species, but not in eusocial rodents like the naked mole-rat. For the current study, the effects of fluoxetine hydrochloride (FLX) on status-specific behaviours of subordinates (Experiment 1) and queens (Experiment 2) were evaluated both in-colony and in a social-pairing paradigm to investigate how the serotonergic system influences aggression in this species. In accordance with our main hypothesis, chronic treatment of FLX attenuated the frequency and duration of aggression in queens, but not subordinates, when paired with an unfamiliar conspecific. Further exploration of pharmacological manipulation on status-specific behaviours of this eusocial species may elucidate the neurobiological mechanisms underlying their unique and rigid social hierarchy.