Elsevier

Hormones and Behavior

Volume 54, Issue 3, August 2008, Pages 347-354
Hormones and Behavior

Review
Reverse engineering the lordosis behavior circuit

https://doi.org/10.1016/j.yhbeh.2008.03.012Get rights and content

Abstract

Reverse engineering takes the facts we know about a device or a process and reasons backwards to infer the principles underlying the structure–function relations. The goal of this review is to apply this approach to a well-studied hormone-controlled behavior, namely the reproductive stance of female rodents, lordosis. We first provide a brief overview on the considerable amount of progress in the analysis of female reproductive behavior. Then, we propose an analysis of the mechanisms of this behavior from a reverse-engineering perspective with the goal of generating novel hypotheses about the properties of the circuitry elements. In particular, the previously proposed neuronal circuit modules, feedback signals, and genomic mechanisms are considered to make predictions in this manner. The lordosis behavior itself appears to proceed ballistically once initiated, but negative and positive hormonal feedback relations are evident in its endocrine controls. Both rapid membrane-initiated and slow genomic hormone effects contribute to the behavior's control. We propose that the value of the reverse-engineering approach is based on its ability to provide testable, mechanistic hypotheses that do not emerge from either traditional evolutionary or simple reductionistic perspectives, and several are proposed in this review. These novel hypotheses may generalize to brain functions beyond female reproductive behavior. In this way, the reverse-engineering perspective can further develop our conceptual frameworks for behavioral and systems neuroscience.

Introduction

Developing explanations of mammalian behaviors with the highest level of mechanistic accuracy and conceptual depth has required choosing behavioral topics that are simple and straightforward enough that serious progress toward understanding mechanisms can be made. A useful example among mammalian behaviors is the simple mating behavior typical of female quadrupeds, lordosis behavior (Pfaff, 1999). Several factors have led to rapid progress in explaining mechanisms for steroid hormone dependent sex behaviors. Steroid sex hormones, being small rigid molecules, have lent themselves to receptor binding studies and other analyses using all the tools of biochemical endocrinology and steroid pharmacology. Steroid hormone receptors, being transcription factors, have allowed neurobiologists to use molecular endocrine techniques to advantage. Moreover, the relatively simple inducing stimuli and stereotyped responses that comprise rodent mating behavior have facilitated neurophysiological analysis and reliable data collection. The fact that many animals perform complete mating behaviors naturally, without lengthy learning protocols, in the laboratory has also helped. All of these factors have permitted scientists studying hormones and behavior to apply biophysics and molecular biology to the understanding of behavioral mechanisms. Currently, this understanding ranges from our knowledge of the lipophilic pits that constitute the ligand binding domains of steroid receptors, measured in angstroms, to the seasonality of reproduction, detected by animals as the yearly variation in photoperiod. As a result, work on lordosis has been prominent both in neurophysiological and molecular genetic explorations into the mechanisms of complete, natural mammalian behaviors.

Within this field of work, extensive quantitative and mechanistic data have been gathered with respect to the control of lordosis behavior. The present review proposes an engineering perspective to the understanding of this behavior. Reverse engineering is an approach newly applied to systems biology in which the scientist looks at the finished product and forms hypotheses about the functionality of the components and the relations between components. The finished product is usually a process that is being dynamically controlled. For example, the reverse-engineering approach has been proposed as a way to understand biological complexity (Csete and Doyle, 2002), especially the complexities of tissue-specific gene expression (de Magalhaes and Toussaint, 2004, Grigorov and van Bladeren, 2007, Schadt and PY, 2006). In our case, the final product is the suite of physiological and behavioral changes that occur during the sexually receptive period as they relate to lordosis. This approach has not been systematically applied to mechanisms by which the brain controls behavior. The facts reviewed in this paper have been published before; this review provides a new way of gleaning insights from that knowledge.

A value of the reverse-engineering process is that it forces us to assess neurobehavioral mechanisms according to how those mechanisms may highlight previously unappreciated constraints based on neural circuitry, social behavior, and/or the timing of neurohormonal action. It may be contrasted in some ways with an evolutionary approach, which may speculate about selective pressures, generating hypotheses that are difficult to test. It is also different than simple reductionistic approaches aimed at divining proximate mediators of behavior. Both evolutionary and reductionistic approaches have provided numerous insights into the biological basis of female mating behavior, and our understanding of this neurobehavioral system may be complemented with the reverse-engineering approach. In fact, reverse engineering is only applicable in a rigorous fashion when there is a firmly established body of knowledge from which to generalize about mechanistic functions. This requirement limits the scope of this conceptual review; the lordosis response is a heavily studied behavior with many published findings. Some associated changes in brain function, such as cognition and reward, may be outside the scope of this paper. This is not to say that our knowledge of lordosis is complete; however, it has reached a level sufficient for making functional inferences. Reverse engineering can be thought of as a particularly demanding stage of systems biology analysis. The goal of this review is to surmise, for the first time with a mammalian behavior, and with as much precision and detail as possible, the organizing principles manifest in the lordosis circuitry.

The neurobiological system of lordosis behavior includes many of the common features that are the focus of reverse-engineering analyses. For example, both technological and biological complex systems routinely depend on modularity. Modules are component parts that interface with other modules, and protocols are the rules that manage the relations between the modules. In complex systems, these protocols become layered, involving feed back signaling. Reverse engineering often considers that complex systems face a trade-off between robustness and complexity. These elements of reverse-engineering analysis can be readily translated to current thinking about the lordosis system.

The sections below will consider several aspects of lordosis behavior, namely the hierarchical neural network, behavioral feedback mechanisms, and the time course of neurohormonal action. For each of these aspects of lordosis behavior we will consider how the reverse-engineering perspective may lead to new predictions. The utility of the reverse-engineering approach can be judged by its ability to provide testable, mechanistic hypotheses that have not emerged from a simple reductionistic perspective. In addition, these novel hypotheses may relate to brain function beyond the scope of female sexual behavior.

Section snippets

Module analysis of the lordosis circuit

Initial investigations of the lordosis response started with the identification of the brain sites mediating estrogen influences and of the sensory modalities for triggering the behavior, leading to the recognition of the neural circuit that mediates the behavior. Neurophysiological and molecular analyses of this circuit proved that specific biochemical reactions in specific nerve cell groups in the mammalian brain govern a specific behavior.

Taking the perspective of evolutionary and

Feedback and feedforward systems in lordosis behavior

Once contacted by the male, the female rat's lordosis behavior proceeds in a ballistic fashion, or not at all, depending on the state of the circuit. In less than 50 ms following cutaneous stimuli from the male, the female has begun the vertebral dorsiflexion that constitutes lordosis behavior (Pfaff and Lewis, 1974). Reflecting on this rapid response, as a simple postural change, lordosis does not require the negative feedback guidance that more intricate responses involving visuo-motor

Kinetics of hormone action

A wide range of time constants governs both the molecular mechanisms of sex hormone actions in cells and the controls over lordosis behavior (Vasudevan et al., 2005). In many behavioral experiments, animals are treated with two pulses of estradiol treatment to mimic the chronic exposure that occurs in intact females. In terms of cellular mechanisms, lordosis behavior depends on slow transcriptional steps in the cell nucleus (Fig. 2), preceded by fast, membrane-initiated estrogenic actions (Fig.

Summary and outlook

This project has focused our attention on some features of the lordosis behavior circuitry as a first attempt at a reverse-engineering approach. Eleven new specific and testable hypotheses have been developed regarding the modular design of the lordosis behavior circuit and how it pertains to feedback systems and the control of the behavior across various time domains.

It was necessary to have picked a behavior simple enough for extensive mechanistic analysis. As a result, we can explain

References (40)

  • RoyE.J.

    Inhibition of sexual receptivity by anesthesia during estrogen priming

    Brain Res.

    (1985)
  • SchadtE.E. et al.

    Reverse engineering gene networks to identify key drivers of complex disease phenotypes

    J. Lipid Res

    (2006)
  • VasudevanN.

    Integration of steroid hormone initiated membrane action to genomic function in the brain

    Steroids

    (2005)
  • AdlerN.T.

    The behavioral control of reproductive physiology

  • BlandauR.

    The length of heat in the albino rat as determined by the copulatory response

    Anat. Rec.

    (1941)
  • CalizoL.H. et al.

    Estrogen selectively induces dendritic spines within the dendritic arbor of rat ventromedial hypothalamic neurons

    J. Neurosci.

    (2000)
  • CalizoL.H. et al.

    Estrogen-induced dendritic spine elimination on female rat ventromedial hypothalamic neurons that project to the periaqueductal gray

    J. Comp. Neurol.

    (2002)
  • CalizoL.H. et al.

    Hormonal–neural integration in the female rat ventromedial hypothalamus: triple labeling for estrogen receptor-a, retrograde tract tracing from the periaqueductal gray, and mating-induced fos expression

    Endocrinology.

    (2003)
  • ChungS.K.

    Estrogen-induced alterations in synaptic morphology in the midbrain central gray

    Exp. Brain Res.

    (1988)
  • Cohen, R.S., Pfaff, D.W., 1981. Ultrastructure of neurons in the ventromedial nucleus of the hypothalamus in...
  • Cited by (0)

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