Elsevier

Brain Research

Volume 1126, Issue 1, 18 December 2006, Pages 109-121
Brain Research

Research Report
From gene networks underlying sex determination and gonadal differentiation to the development of neural networks regulating sociosexual behavior

https://doi.org/10.1016/j.brainres.2006.07.031Get rights and content

Abstract

Genes are not expressed in isolation any more than social behavior has meaning outside of society. Both are in dynamic flux with the immediate environment that the gene/individual finds itself, which in turn establishes the timing, pattern, and conditions of expression. This means that complex behaviors and their genetic underpinnings should be viewed as a cumulative process, or as the result of experiences up to that point in time and, at the same time, as setting the stage for what will follow. The evidence indicates that as experiences accumulate throughout life, early experiences shape how genes/individuals will respond to later experiences, whereas later experiences modify the effects of these earlier experiences. A method of graphically representing and analyzing change in gene and neural networks is presented. Results from several animal model systems will be described to illustrate these methods. First, we will consider the phenomenon of temperature-dependent sex determination in reptiles. We will illustrate how the experience of a particular temperature during a sensitive period of embryogenesis sculpts not only the patterns of expression of genes involved in sex determination and gonadal differentiation but also the morphological, physiological, neuroendocrine, and behavioral traits of the adult phenotype. The second model system concerns the effects of the sex ratio in the litter in rats, and the genotype ratio in the litter of transgenic mice, on the nature and frequency of maternal care and how this in turn influences the patterns of activation of identified neural circuits subserving the offspring's sociosexual behavior when it is an adult.

Introduction

The above quotes impress upon us that at any point in time all traits, whether it is an organism's behavior, its physiology, or the patterns of gene expression during the formation of a tissue, have a history that has shaped its immediate expression. This history can be on a scale of seconds and minutes, an individual's lifetime, over generations and ultimately through evolutionary time. The challenge then is how to study this constant yet ever changing complexity.

Most scientists take the strategy of changing single variables and observing the outcome, assuming incorrectly that the observed result is due to the manipulation and the measured variable alone. Although it has long been appreciated that the product(s) result from the dynamic and reciprocal exchange between the trait and its external environment and internal milieu, efforts to study the process have usually been identified with individual scientists rather than to schools of thought. This minority approach of casting the net wide to determine how change affects the web of causative elements has had a disproportionate impact on scientific advances.

We offer here several case studies from our recent work in developmental genetics and developmental neuroscience to illustrate one such attempt. Rather than incorporating many variables, we limited our experiments to a handful. As will be evident, even this very focused strategy reveals emergent properties within systems that have not been sufficiently appreciated. The phenomena of environmental regulation of genetic cascades in temperature-dependent sex determination (TSD) and the role of experience in shaping the neural substrates that underlie sociosexual behavior in adult reptiles and mammals serve as particularly good examples of how this interaction modifies the adult phenotype. In both epigenetic factors (meaning outside the gene) play a fundamental role in how the individual develops in the way that it does. We will see that although the triggers of sex determination may differ, the mechanisms and processes that lead to a functional male or female are similar. Alternatively, we will see how similarities in behavioral expression can be underpinned by very different patterns of neural activity.

Section snippets

Genetic cascades and neural networks

Complex traits are not particularly susceptible to conventional analysis. A first order strategy unraveling this complexity has been to single out a particular trait(s), in this instance genes and brain nuclei and their respective roles in sex determination and sociosexual behavior, and apply any of an increasing variety of sophisticated methods to study their function. Although very successful in its own right, this approach has created problems for understanding the developmental and

The functional landscape method

Any method should have certain attributes. Principally, it should accommodate the possibility that the different components may have different scales of measurement, enable the measurement of the network of interrelated components as a whole, and how it changes with time or manipulation. A new method is illustrated here that uses both published and unpublished data derived from experiments on reptiles and mammals.

The steps of this analytic procedure are as follows.

First, the elements are

Case study: sex determination and gonadal differentiation

Vertebrates exhibit two forms of sex determination, genotypic sex determination (GSD), and environmental sex determination (ESD). The most thoroughly studied is GSD, a process in which the sex of the individual is established at fertilization with the union of the male and female gametes and the inheritance of a specific gene(s) from one of the parents. In mammals this is Sry. Thereafter, a reliable and regular series of molecular events unfold that leads to the development of testes or

Case studies: neural networks and the role of experience in their organization

How does experience modify the neural mechanisms underlying sociosexual behavior? In particular, how do experiences early in life and later in adulthood interact to affect adult sexual behavior and the underlying neural circuits? The proposition that embryonic experience interacts with adult experience in shaping behavioral phenotype is simple enough conceptually: adult animals change their behavior in response to experience, and the nature of this change depends on various factors, some of

Conclusions

In vertebrates, a handful of genes is known to be centrally involved in the processes of sex determination and gonadal differentiation. About the same number of brain nuclei comprise the neural network that underlies vertebrate social behaviors. In both processes a discrete number of genes and brain nuclei, respectively, are not only involved in the final product, but they all have established interactions. This makes it feasible to depict the dynamic interaction among components of each system

Acknowledgments

This work was supported in part by NIH grants MH57874 and MH068273 (DC), MH 068273 and the CHIR (AF), and MH62147 and the 21st Century COE program, Japan (SO). We thank the following students and colleagues without whose tireless efforts this work would never have seen the light of day: N. Matthews, F. Gonzalez-Lima, Raymond Porter, Mary Ramsey, Christina Shoemaker, Brian Dias and Kimberly Hillsman (Texas); C. de Medeiros, S. Rees, M. Llinas, and B. Bardo (Canada); and S. Luk, L. Murphy, N.

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