Jeffrey R. Alberts - US grants

Behavioral development of the Norway rat is analyzed from a novel perspective in which behavioral and physiological exchanges between mother and offspring serve as ontogenetic mechanisms that coordinate parent-offspring relations, and establish perceptual preferences in both parent and young that guide the expression and development of behavior. Thermotactile stimulation is analyzed as a component of their contact interactions, and the behavioral and physiological effects of conductive and convective heat exchanges are evaluated empirically. Thermal energy is studied as a "primary metabolic commodity" that has regulatory effects on parent and offspring and which may serve to establish learned associations with other cues. Behavioral observations of mother-litter interactions are used to establish quantitative assessments of body surface area for heat transfer, and direct measures of thermal flux are made. The consequences of these exchanges on the development of olfactory and filial preferences are studied. Changes in salt appetite associated with the maternal condition are analyzed in terms of perceptual changes and a consequence of specific influences of the offspring on the dam. The control of maternal perception and maternal behavior are analyzed in the context of resource exchange and offspring control. Chemical analyses of pup urine will be made for preliminary isolation of a gender-specific factor that regulates maternal licking of young. Modification of reciprocal exchanges are used to define transitions in the parent-offspring relationship. Comparative studies with Peromyscus californicus, a species that displays bi-parental care are used to test a mutualistic model of parental behavior. New studies of energetic controls of weaning are proposed for the Norway rat.

The behavioral life of a young mammal begins within a uterine environment, and makes an abrupt transition (via birth) to a markedly different postnatal environment. We propose a program of research designed to elucidate sensory experience in the rat during late fetal and early postnatal environment - the perinatal period (El5-P5) - as a key to the origins of behavioral organization. The proposed experiments test hypotheses of sensory development derived from adaptive problems faced by the fetus in the uterine environment, and from corresponding adaptational challenges encountered by the newborn in the postnatal neonatal niche, immediately after parturition. From this perspective, we propose to determine onsets of function for the tactile, chemical, vestibular, and thermal senses. Sensory function will be measured by heartrate and behavioral responses. Based on analyses of ontogenetic adaptations to their developmental niches, we hypothesize and test predicted patterns of inter-modal development of sensitivity, and intra-modal maturation in different body regions. Novel studies of behavior of pregnant and lactating rats will help identify kinds and amounts of stimulation to which offspring are normally exposed. These experiments should establish a theoretically-framed database on the psychobiology of fetal and neonatal life that will support additional studies of early behavioral structure and learning. The proposed research can make significant contributions to our basic understanding of neurobiological development, and to applied issues concerning care and management of premature and at-risk human infants.

minority institution research support; secondary schools;

DESCRIPTION (provided by applicant): Sociality is the dimension of behavior that brings organisms into association with others, especially other members of one's species and affords all the vital interactions that represent phenomena such group affiliation, mate choice, parental behaviors, information exchange, and altruism. Sociality exists on the level of the individual and on the level of the group, and each has a separable, but interrelated development. The proposed research is designed to define and identify the onset of sociality in Mus musculus, the major model mammal serving the NIH Roadmap. We propose a program of research that will employ observational, experiential, physiological, genomic and neuroendrocrine approaches to recognizing when social responses are first expressed by infant mouse pups, how their social behavior becomes directed at other mice, and the rules that govern individual and group behavior. The Specific Aims of the proposed research include: establishing for the C57 strain of laboratory mouse, a set of group and individual phenomena that represent their early social behaviors; creating parametric, foundation data on metabolic effort by individuals and groups so that physiological (especially thermal) effects of contact behavior can be separated from non-thermal, social affiliations. Throughout the research, we will also invoke selected genetically-engineered (knock out) mice to both test specific hypotheses concerning the roles of cutaneous temperature sensation and the central oxytocin in the formation and expression of filial behavior. Sociality in individual development will be analyzed, especially the development of olfactory preferences that make specific individual's filial responses. Novel olfactory isotopes will be used to discover the developmental determinants that derive from specific experiences in the nest with mother and littermates. These constitute probes into how natural experiences serve as learning mechanisms in behavioral development. Finally, we will provide both global and specific measures of maternal behavior in the C57 mother mouse, for these data and their methods are needed for complete analyses of genetic and other experimental contributions to development, since many of these manipulations can operate by altering in maternal behavior. Maternal responses to genomically-altered litters and individuals will be studied to test these ideas. PUBLIC HEALTH RELEVANCE: The importance of the proposed research will be seen first in its contribution to linking objective and quantitative metrics of social behavior to modern knowledge of gene expression and endocrine processes in the brain. This linkage in a mouse model will provide a needed research tool for testing treatments for the many forms of mental illness, such as the autism spectrum disorders and schizophrenia, that involve fundamental disruptions in social processes and social responses.

DESCRIPTION (provided by applicant): The meeting of the American Society for Gravitational and Space Biology society is the singular, annual event for this interdisciplinary field. The meeting will be composed of three invited symposia, paper sessions, poster sessions, and workshops including sessions on science education using space biology as a motivating topic. Spaceflight effects on immune function, host immunity, microbial virulence, as well as novel approaches to vaccine development will be a featured topic at the meeting, reflecting excitement stirred by recent results. Because the microgravity environment of space presents special opportunities for understanding the translation of gravity-related stimuli into perception, another symposium will address neurophysiological, developmental, and evolutionary data and concepts for vestibular plasticity, which have implications for biomedical problems of space adaptation, movement control and remediation as well as aging. These considerations apply to a host of related topics, including bone osteoporosis, skeletal muscle atrophy, and cardiovascular atrophy. Bioengineering issues and cellular science will also be represented by a forward-looking symposium addressing tissue engineering, synthetic biology, and the use of bioreactors. Submitted papers and posters will cover all these topics. Student involvement and effective science education are also emphasized with the conference activities. We seek partial support for symposia speakers, student travel, poster display rental, and transport to activities at the nearby NASA center. PUBLIC HEALTH RELEVANCE: The meeting of the American Society for Gravitational and Space Biology society will host three symposia. The speakers will cover fundamental and biomedical-related research, including spaceflight effects on immune competence and microbe virulence, microgravity effects on neural plasticity as well as bone and muscle adaptation, photobiology and plant growth, and bioengineering studies of tissues and synthetic biology on cellular levels.

DESCRIPTION (provided by applicant): Autism spectrum disorders (ASDs) are characterized by a suite of cognitive and social deficits, as well as by a range of somatic abnormalities, including mitochondrial, metabolic, and thermoregulatory deficits. The metabolic features of ASDs have received little attention from researchers investigating ASD-related phenotypes in mouse models. In addition, few researchers have taken a developmental approach to modeling ASD-related social deficits, despite the ASDs being understood as developmental disorders. Recent evidence indicates that several mouse models of social dysfunction (e.g., oxytocin and oxytocin receptor knockouts) have striking metabolic and thermoregulatory deficits that have gone unnoticed in previous studies of ASD-related phenotypes. A framework for relating social and metabolic deficits is lacking, and it is unclear to what extent the social deficits displayed b these models may relate to disrupted metabolic (e.g., thermal) homeostasis. We will test a framework in which social and metabolic phenotypes are seen as intimately related across developmental timescale, and in which animals with compromised metabolic and/or thermoregulatory homeostasis are predicted to exhibit deficits in basic aspects of social functioning. We will employ a suite of developmental, genetic, and pharmacological methods to elucidate these relations, and will focus on brown adipose tissue (BAT) thermogenesis as a model system for relating social and metabolic phenotypes in mouse models. First, we will track individual developmental trajectories in mice from high- and low-social strains, employing a battery of metabolic and social/emotional measures during development, with the aim of exploring the impact of naturally occurring variation in metabolic phenotypes on variation in social and emotional phenotypes. Next, we will characterize social and metabolic functioning in a number of mouse lines and genetically-engineered gene 'knockout' constructs selected for having deficits in either social or metabolic functioning, with the aim of testing our hypothesis that metabolic and social phenotypes manifest co-variations within and across mouse strains and constructs. We will also test the contribution of thermal conditions during animal rearing and testing to performance on commonly used tests of social and emotional functioning in several mouse models of ASD-related phenotypes already known to possess significant thermoregulatory deficits. This experiment will clarify the role that thermoregulatory deficits pla in the social and emotional deficits displayed by these mice. Lastly, we will examine the hypothesis that metabolic heat generated by BAT plays a significant role in mediating the prosocial effects of oxytocin in mouse models using pharmacological manipulation of BAT and oxytocin functioning. These experiments will greatly add to our knowledge of the development and expression ASD- related phenotypes in mouse models, and will have high translational value, given the presence of poorly understood metabolic deficits in ASD.

Virtually all animals, including humans, play host to a wide range of microorganisms such as bacteria and fungi that function within cells, tissues, and organs. Many of these microorganisms reside within the gut. Recent evidence suggests that this 'gut microbiome' exerts a surprising and powerful influence on the normal brain and on behavior in both adults and the young. How the gut microbiome influences the brain and behavior, however, is essentially unknown. This research will test a novel mechanism by which the gut microbiome may contribute to the development of offspring sociality by focusing on the shared mother-offspring microbiome in dwarf hamsters. The goal of the proposed research is to test the idea that disruption of the maternal microbiome, via antibiotic administration, alters the diversity and composition of the mother's gut microbiome and consequently affects the development of normal social behavior and related physiological parameters in her offspring. This research will also test whether the restoration of the maternal gut microbiome returns social behaviors to normal. Lastly, these studies will examine the role of bi-parental (i.e., mother and father) behaviors in preventing the adverse effects of a disrupted maternal microbiome on offspring social behavior. Collectively, these studies will provide fundamental knowledge of the basic mechanisms by which the maternal microbiome influences the development of offspring sociality. An understanding of these mechanisms will provide important basic knowledge that may ultimately inform treatment and prevention of debilitating disorders characterized by deficits of social functioning. In addition to training graduate student researchers, undergraduates in Indiana University's Research Experience for Undergraduates program and a local middle school teacher and middle school class will take part in the research. The middle school students will participate in activities focused on soil and gut microbes at the local Marble Hill Farm.

The precise physiological mechanisms underlying microbiome effects on the brain and social behavior, however, remain unknown. This research employs an animal model to elucidate the impact of maternal microbiome status on the development of offspring sociality as well as the mechanisms underlying observed microbiome-brain-behavior relationships. Specifically, the experiments utilize animals that display either bi-parental (i.e., both maternal and paternal) care or uni-parental (i.e., exclusively maternal) care to tease apart their relative contributions to offspring development. The goal of the proposed research is to test the specific hypotheses that: 1) disruption of the maternal microbiome via antibiotic administration alters the diversity and composition of gut microbiota and consequently offspring sociality, stress responsivity, and cytokine profiles; 2) disruption of neuroendocrine and/or neuroimmune systems mediates, at least in part, the effects on social behaviors; 3) repletion of the gut microbiome via fecal transplants restores normal social behaviors; and 4) bi-parental care modulates these effects by providing additional contributions of paternal behavior to buffer offspring. The proposed studies will provide valuable insight on the basic mechanisms of microbiome influences on maternal-offspring behavioral interactions, the role of paternal behaviors in buffering the influences of maternal microbiome disruption on offspring behavior, as well as the development of social behaviors more broadly.