The common theme of research projects in the Sisk Lab is the influence of steroid hormones
on nervous system structure and function. Gonadal steroids, such as testosterone, estrogen,
and progesterone, profoundly affect neuronal activity, connectivity within neural circuits, and
behavior at different stages of life, including early neural development, puberty, and in adulthood.
Neural and behavioral responses to steroid hormones vary with developmental stage. Our work focuses
on the role of pubertal hormones in shaping development of the adolescent brain and maturation of
adult behaviors, and it contributes to an understanding of the ways and extent to which the capacity
for functional plasticity within the nervous system changes across the lifespan. Research in the Sisk
Lab is a combination of neuroendocrinology, developmental neurobiology, and behavioral neuroscience.
We employ a variety of experimental techniques, ranging from analysis of gene expression to analysis
The Behavioral Neuroendocrinology of Puberty and Adolescence
A major research effort in the Sisk Lab is directed toward understanding the neural, endocrine, and behavioral changes that take place during puberty and adolescence. Adult cognition, social behaviors, responses to sensory stimuli, and responses to environmental stressors are remarkably different from those of the juvenile organism. Thus, the juvenile-to-adult transition is a fundamental period of neural development, and we believe it involves many of the same steroid-dependent and steroid-independent developmental processes that occur during early neural development. We think of this metamorphosis as having two major and distinguishable elements. Puberty is maturation of the hypothalamic-pituitary-gonadal axis, which involves activation of the neurons that release gonadotropin releasing hormone (GnRH). GnRH release at the time of puberty results in gonadal maturation and fertility. Adolescence is maturation of adult behaviors, many of which are influenced by the gonadal steroid hormones that are produced during puberty.
We've used the male golden hamster as a model system for studying both puberty and adolescence. GnRH neurons in prepubertal and adult hamsters are different in a variety of ways, including the level of GnRH mRNA expression, how GnRH neurons are regulated by endocrine feedback loops, and whether they are activated by chemosensory stimuli (Richardson et al, 1999; Parfitt et al, 1999; Richardson et al, 2002; Richardson et al, 2004a; Richardson et al, 2004b). Mating behavior in adult male hamsters is dependent on both the presence of steroid hormones and chemosensory cues from the female. We found that, prior to puberty, mating behavior cannot be elicited in juvenile males, even when they are provided with the appropriate steroids and the female chemosensory cues (Meek et al, 1997; Romeo et al, 2001; Romeo et al, 2002). Thus, the way the nervous system responds to these external and internal stimuli is very different before and after puberty. The neural circuit underlying male reproductive behavior in the hamster is well-characterized. We've found that steroid receptors are present and functional prior to puberty, suggesting that the steroid-sensitive machinery is in place in the juvenile male (Romeo et al, 1999a; Romeo et al, 1999b; Romeo et al, 2002). However, an important difference between prepubertal and postpubertal males is in their neural responses to the female pheromone that facilitates behavior (Romeo et al, 1998; Schulz et al, 2003). Within a few minutes of exposure to female pheromone, adults show an increase in LH and testosterone secretion and an increase in dopaminergic activity in the preoptic area. Neither response occurs in juvenile males. This suggests either that the chemosensory cue does not have the same meaning to the animal before and after puberty, or that the appropriate integration of steroidal and chemosensory information required for expression of mating behavior is not taking place prior to puberty. We are currently exploring how this developmental change in response to female chemosensory stimuli takes place, focusing on the adolescent development of dopaminergic systems.
We are also investigating whether puberty is a critical period for the organization of neural circuits and behavior by gonadal steroids. Our experiments show that if gonadal hormones are removed before puberty, then both male and female reproductive behavior and agonistic behaviors are compromised, even after hormones are replaced in adulthood (Schulz et al, 2004), providing indirect evidence that hormones must be present during adolescence for the expression of adult-typical behavior. Current work is directly testing the hypothesis that adolescence is a sensitive period for organization of the nervous system by steroids.
The Neurobiology of Adolescent Brain Development
We have focused on the amygdala in our initial studies examining structural change within the brain during adolescence. The amygdala is a temporal lobe structure that is key for evaluation of socially relevant sensory stimuli, and it is an integral part of the neural circuit that mediates steroid-dependent social behaviors. We’ve documented neuroanatomical changes during adolescence in nuclei of the amygdala, including changes in overall regional volume and synaptic pruning (Romeo and Sisk, 2001; Zehr, et al, J. Neurobiology, in press, 2005). Current work is establishing whether these structural changes are related to the changing steroid levels during puberty, or whether they occur independently of steroid hormones.
Another project is focusing on the role of steroid hormones in the neurogenesis and gliogenesis that occurs during adolescent brain development. One area that we are studying is the anteroventral periventricular nucleus, a hypothalamic region that is larger in females than in males and that is functionally related to the ability of females, but not males, to show a preovulatory surge of gonadotropin secretion in response to estrogen. The sexual dimorphism in AVPV size emerges during pubertal development, and using BrdU as a marker of the time of cell birth, we’ve found that the number of cells born in the AVPV during puberty is greater in females than in males, suggesting that the addition of new cells is a mechanism that contributes to the sexual dimorphism in overall size of AVPV.
Research Projects Related to Human Adolescence
Our work has direct implications for human adolescent development and human mental health. First, a number of sex-biased psychopathologies, such as eating disorders, depression, and schizophrenia emerge during adolescence, suggesting both a hormonal and developmental contribution to their etiology. Second, the influence of steroids on developmental processes in the human adolescent nervous system is altered or perturbed by a variety of circumstances, including the delay of gonadal development brought about by eating disorders, extreme exercise, or disease, the abuse of anabolic androgenic steroids, and exposure to environmental endocrine disruptors. We hope to establish the temporal and developmental parameters within which steroid hormones impact nervous system during puberty in order to fully define and understand periods of vulnerability for the development of behavioral pathologies.
A relatively new line of research examines the effect of exposure to anabolic androgenic steroids during puberty and adolescence. Anabolic steroids are used by athletes and teenagers to promote muscle growth and enhance athletic performance. These synthetic hormones also have adverse effects on the nervous and reproductive systems. Using the male hamster model, we are currently investigating the effects of anabolic steroids on aggressive and reproductive behaviors. Our initial findings are that anabolic steroids increase both aggressive and reproductive behavior in adolescent males. Future studies will compare the effects of anabolic steroids in adolescent males with those in adults, and will determine whether adolescent exposure to anabolic steroids has long-lasting effects on behavior that persist beyond the period of drug exposure.
Together with Dr. Kelly Klump at MSU, we are beginning to investigate how the timing of puberty alters adult behavior in humans. Dr. Klump studies genetic and environmental factors that contribute to the development of eating disorders such as anorexia nervosa and bulimia. Dr. Klump has found that genetic factors and possibly estrogen contribute to the emergence of eating disorders in adolescent girls. Our initial experiments are examining whether behavioral traits of young women and men are altered by early or late onset of puberty. Initial results indicate that early onset of puberty in both women and men is associated with higher scores on scales of eating disordered behavior.
New cells are added to AVPV during puberty in both males and females rats. Our finding that the number of BrdU-labeled cells in females is almost twice that of males suggests that addition of new cells contributes to the development and/or maintenance of the sexual dimorphism in AVPV size.
Golgi-impregnated neuron in the medial amygdala (below left) and higher magnification showing dendritic spines (below right). Analysis of Golgi-impregnated neurons of male hamsters in different stages of adolescent development provide evidence for structural changes in the medial amygdala, including axon origin, loss of primary dendrites, and a decrease in spine density (schematic diagram, neuron from prepubertal animal on the left, neuron from late adolescent animal on the right).
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