The Pioneer Neuropharmacologist Alfred Fröhlich (1871-1953) and the Origins of Neuroendocrinology: A Sesquicentennial Remembrance.

The birth of neuroendocrinology as a scientific discipline is traced back to 1900-1901, when Joseph Babinski, Alfred Fröhlich, and Harvey Cushing independently identified adiposogenital dystrophy (Fröhlich syndrome), and related gonadal underdevelopment and obesity to a tumor near the pituitary gland. This discovery prompted decades of research into the brain mechanisms responsible for the control of peripheral metabolism and endocrine functions. On the occasion of the 150th anniversary of Fröhlich's birth, this study traces the origins of his intellectual formation and his association with renowned contemporaries in Austria, England, Italy, and finally Cincinnati, Ohio, where he sought refuge after Austria's annexation by Nazi Germany. Fröhlich interacted with seminal figures in biomedicine, including Lothar von Frankl-Hochwart, Hans Horst Meyer, Ernst Peter Pick, Harvey Cushing, John Newport Langley, and the Nobel laureates Charles Scott Sherrington and Otto Loewi. Alfred Fröhlich, one of the 20th century's most emblematic physicians, left his mark on neurophysiology and neuropharmacology with important works, and published authoritative manuals of drug dispensing and clinical therapy. He confronted the calamities of two World Wars with remarkable resilience like many of his Viennese colleagues who, overcoming the constraints of National Socialism, settled overseas to fulfil their calling as physicians, researchers, and teachers.

[From neuroendocrinology to cell biology: Andrée Tixier-Vidal]. / De la neuroendocrinologie à la biologie cellulaire : Andrée Tixier-Vidal (1923­2021).

This article relates the life, career and main scientific achievements of a pioneer in neuroendocrinology and French cell biology research, Mrs Andrée Tixier-Vidal, who passed away in December 2021. After her first works on hypophyseal-thyroid neuroendocrine axis, in birds then in mammals, Andrée Tixier-Vidal devoted herself then her group at the College of France to the histophysiological study of adenohypophysis and namely of prolactin (PRL) cells. Using in vitro models of organotypic cultures and cultures of GH3 cells, she described up to ultrastructural level the secretory process of PRL and its regulation by TRH. Furthermore, she extended her study to the TRH neurons themselves thanks to original models of in vitro cultures of hypothalamic neurons. Her fundamental and methodological achievements have largely contributed to major knowledge advances in cell biology of the secretion during the last century.

Title: De la neuroendocrinologie à la biologie cellulaire : Andrée Tixier-Vidal (1923­2021). Abstract: Cet article relate la vie, la carrière et l'œuvre scientifique de Mme Andrée Tixier-Vidal, disparue en décembre 2021. Il montre comment, après avoir développé une approche histophysiologique originale de la neuroendocrinologie et tout particulièrement de l'axe hypophyso-thyroïdien, elle a réalisé des travaux pionniers qui ont complètement renouvelé les connaissances sur les neurones hypothalamiques à thyréolibérine (TRH) qui interviennent dans la régulation des cellules à thyréostimuline (TSH), mais également de celles à prolactine (PRL). Le fil conducteur de ses recherches a été la biologie cellulaire de la sécrétion abordée par les techniques morphologiques et cytochimiques sur des modèles originaux de cultures organotypiques d'hypophyse mais aussi de cellules tumorales GH3 et enfin de neurones hypothalamiques. Le rayonnement scientifique de Mme Tixier-Vidal et de son équipe se prolonge encore à travers les multiples générations de chercheurs qui ont eu le privilège de profiter de son dynamisme intellectuel et de son enthousiasme pour la recherche en biologie.

History of hypothalamic research: "The spring of primitive existence".

The central brain region of interest for neuroendocrinology is the hypothalamus, a name coined by Wilhelm His in 1893. Neuroendocrinology is the discipline that studies hormone production by neurons, the sensitivity of neurons for hormones, as well as the dynamic, bidirectional interactions between neurons and endocrine glands. These interactions do not only occur through hormones, but are also partly accomplished by the autonomic nervous system that is regulated by the hypothalamus and that innervates the endocrine glands. A special characteristic of the hypothalamus is that it contains neuroendocrine neurons projecting either to the neurohypophysis or to the portal vessels of the anterior lobe of the pituitary in the median eminence, where they release their neuropeptides or other neuroactive compounds into the bloodstream, which subsequently act as neurohormones. In the 1970s it was found that vasopressin and oxytocin not only are released as hormones in the circulation but that their neurons project to other neurons within and outside the hypothalamus and function as neurotransmitters or neuromodulators that regulate central functions, including the autonomic innervation of all our body organs. Recently magnocellular oxytocin neurons were shown to send not only an axon to the neurohypophysis, but also axon collaterals of the same neuroendocrine neuron to a multitude of brain areas. In this way, the hypothalamus acts as a central integrator for endocrine, autonomic, and higher brain functions. The history of neuroendocrinology is described in this chapter from the descriptions in De humani corporis fabrica by Vesalius (1537) to the present, with a timeline of the scientists and their findings.

Hacia una historia revisada de la teoría organizacional-activacional / Towards a revised history of organisational-activational theory

En las últimas décadas la neuroendocrinología del comportamiento ha pasado de un área marginal de la incipiente revolución neurocientífica a una disciplina bien consolidada, hasta el punto de convertirse en el abordaje estándar para las diferencias y la diferenciación sexual de la conducta. Tanto en los trabajos de historia general de la endocrinología, como en las reviews de la especialidad y las aproximaciones críticas desde el feminismo académico, se ha generado un racconto según el cual la teoría central de la neuroendocrinología, esto es, la Teoría Organizacional Activacional habría sido fundada en 1959 por W. C. Young y sus colaboradores al descubrir los efectos de la testosterona fetal sobre conejillas de indias hembra. En el presente artículo se propone una revisión de tal historia oficial, comenzando con los trabajos de Arnold Berthold, profundizando en los desarrollos endocrinos de los años veinte y treinta del siglo pasado y revisando las disputas entre Young y Beach en los años previos a la publicación del 59. Con esta revisión, se pretende mejorar el conocimiento histórico de la teoría organizacional activacional, lo cual de forma derivada puede ayudar a iluminar algunas polémicas en torno a las explicaciones biológicas de la sexualidad humana

In recent decades, behavioural neuroendocrinology has moved from a marginal area of the incipient neuroscientific revolution to a well-established discipline, to the extent that it has become the standard approach to sexual differences and differentiation in behaviour. In the general historiography of endocrinology, in discipline-specific reviews as well as in critical articles, an official history has been generated according to which Organizational-Activational Theory was founded in 1959 by W. C. Young and his collaborators when they discovered the effects of fetal testosterone on guinea pigs. This article proposes a review of that official history, starting with the works of Arnold Berthold, delving into the endocrine developments of the 1920s and 1930s and reviewing the disputes between Young and Beach in the years leading up to the publication of 1959. This review is intended to improve the historical knowledge of Organizational-Activational Theory, which in turn may help to shed light on some of the controversies surrounding biological explanations of human sexuality

Testosterone administration in human social neuroendocrinology: Past, present, and future.

Over the past 20 years, social neuroendocrinology researchers have developed pharmacological challenge paradigms to assess the extent to which testosterone plays a causal role in human psychological and behavioural processes. The current paper provides a brief summary of this research and offers recommendations for future research examining the neuroendocrine mechanisms underlying human behaviour.

Estrogenic regulation of memory: The first 50 years.

This review highlights fifty years of progress in research on estradiol's role in regulating behavior(s). It was initially thought that estradiol was only involved in regulating estrus/menstrual cycles and concomitant sexual behavior, but it is now clear that estradiol also influences the higher order neural function of cognition. We provide a brief overview of estradiol's regulation of memory and some mechanisms which underlie its effects. Given systemically or directly into the hippocampus, to ovariectomized female rodents, estradiol or specific agonists, enhance learning and/or memory in a variety of rodent cognitive tasks. Acute (within minutes) or chronic (days) treatments enhance cognitive functions. Under the same treatment conditions, dendritic spine density on pyramidal neurons in the CA1 area of the hippocampus and medial prefrontal cortex increase which suggests that these changes are an important component of estrogen's ability to impact memory processes. Noradrenergic, dopaminergic and serotoninergic activity are also altered in these areas following estrogen treatments. Memory enhancements and increased spine density by estrogens are not limited to females but are also present in castrate males. In the next fifty years, neuroscientists need to determine how currently described neural changes mediate improved memory, how interactions among areas important for memory promote memory and the potential significance of neurally derived estrogens in normal cognitive processing. Answering these questions may provide significant advances for treatment of dementias as well as age and neuro-degenerative disease related memory loss.

Hormones and Behavior: An emergent journal.

Hormones and Behavior was founded in 1969 by Frank A. Beach and members of his laboratory. Prior to the founding there was no journal specifically devoted to hormones and behavior. This paper explores how the editorship of the journal has developed over the first 50 years, going from the initial three male editors to the current female editor-in-chief, five associate editors (four men and one women), and a 98 member editorial board consisting of 46 men and 52 women. Early concerns that a specialty journal of hormones and behavior might ghettoize the field did not come to pass and the visibility and impact of the journal has helped to expand the spread of the field, now called Behavioral Neuroendocrinology. This growth accelerated with the creation of the Society for Behavioral Neuroendocrinology in 1996 and the adoption of Hormones and Behavior as the Society's official journal. The growth has been striking with total annual citations going from 1321 per year in 1997 to the current 10,874 annual citations. The journal's impact factor (JIF), 1.42 in 1997, has increased to the current (2018) JIF of 3.95. Over the 50 years of Hormones and Behavior's existence it has emerged as a principle voice of the Hormones and Behavior community. It will be intriguing to see what the next 50 years reveals.

Sexual differentiation of brain and other tissues: Five questions for the next 50 years.

This paper is part of the celebration of the 50th anniversary of founding of the journal Hormones and Behavior, the official journal of the Society for Behavioral Neuroendocrinology. All sex differences in phenotypic development stem from the sexual imbalance in X and Y chromosomes, which are the only known differences in XX and XY zygotes. The sex chromosome genes act within cells to cause differences in phenotypes of XX and XY cells throughout the body. In the gonad, they determine the type of gonad, leading to differences in secretion of testicular vs. ovarian hormones, which cause further sex differences in tissue function. These current ideas of sexual differentiation are briefly contrasted with a hormones-only view of sexual differentiation of the last century. The multiple, independent action of diverse sex-biasing agents means that sex-biased factors can be synergistic, increasing sex differences, or compensatory, making the two sexes more equal. Several animal models have been fruitful in demonstrating sex chromosome effects, and interactions with gonadal hormones. MRI studies of human brains demonstrate variation in brain structure associated with both differences in gonadal hormones, and in the number of X and Y chromosomes. Five unanswered questions are posed as a challenge to future investigators to improve understanding of sexual differentiation throughout the body.

How technical progress reshaped behavioral neuroendocrinology during the last 50 years and some methodological remarks.

The first issue of Hormones and Behavior was published 50 years ago in 1969, a time when most of the techniques we currently use in Behavioral Endocrinology were not available. Researchers have during the last 5 decades developed techniques that allow measuring hormones in small volumes of biological samples, identify the sites where steroids act in the brain to activate sexual behavior, characterize and quantify gene expression correlated with behavior expression, modify this expression in a specific manner, and manipulate the activity of selected neuronal populations by chemogenetic and optogenetic techniques. This technical progress has considerably transformed the field and has been very beneficial for our understanding of the endocrine controls of behavior in general, but it did also come with some caveats. The facilitation of scientific investigations came with some relaxation of methodological exigency. Some critical controls are no longer performed on a regular basis and complex techniques supplied as ready to use kits are implemented without precise knowledge of their limitations. We present here a selective review of the most important of these new techniques, their potential problems and how they changed our view of the hormonal control of behavior. Fortunately, the scientific endeavor is a self-correcting process. The problems have been identified and corrections have been proposed. The next decades will obviously be filled with exciting discoveries in behavioral neuroendocrinology.

The behavioral neuroendocrinology of maternal behavior: Past accomplishments and future directions.

Research on the neuroendocrine-endocrine-neural regulation of maternal behavior has made significant progress the past 50 years. In this mini-review progress during this period has been divided into five stages. These stages consist of advances in the identification of endocrine factors that mediate maternal care, the characterization of the neural basis of maternal behavior with reference to endocrine actions, the impact of developmental and experiential states on maternal care, the dynamic neuroplastic maternal brain, and genes and motherhood. A final section concludes with a discussion of future directions in the field of the neurobiology/neuroendocrinology of motherhood.

New concepts in the study of the sexual differentiation and activation of reproductive behavior, a personal view.

Since the beginning of this century, research methods in neuroendocrinology enjoyed extensive refinements and innovation. These advances allowed collection of huge amounts of new data and the development of new ideas but have not led to this point, with a few exceptions, to the development of new conceptual advances. Conceptual advances that took place largely resulted from the ingenious insights of several investigators. I summarize here some of these new ideas as they relate to the sexual differentiation and activation by sex steroids of reproductive behaviors and I discuss how our research contributed to the general picture. This selective review clearly demonstrates the importance of conceptual changes that have taken place in this field since beginning of the 21st century. The recent technological advances suggest that our understanding of hormones, brain and behavior relationships will continue to improve in a very fundamental manner over the coming years.

From serendipity to clinical relevance: How clinical psychology and neuroscience converged to illuminate psychoneuroendocrinology.

Dirk Hellhammer and his colleagues have played a major role in creating the field of psychoneuroendocrinology from their roots in psychology. In this review, using examples from the history of the McEwen laboratory and neuroscience and neuroendocrinology colleagues, I summarize my own perspective as to how the fields of neuroscience and neuroendocrinology have contributed to psychoneuroendocrinology and how they converged with the contributions from Dirk Hellhammer and his colleagues.

Thirty years of neuroendocrinology: Technological advances pave the way for molecular discovery.

Since the 1950s, the systems level interactions between the hypothalamus, pituitary and end organs such as the adrenal, thyroid and gonads have been well known; however, it is only over the last three decades that advances in molecular biology and information technology have provided a tremendous expansion of knowledge at the molecular level. Neuroendocrinology has benefitted from developments in molecular genetics, epigenetics and epigenomics, and most recently optogenetics and pharmacogenetics. This has enabled a new understanding of gene regulation, transcription, translation and post-translational regulation, which should help direct the development of drugs to treat neuroendocrine-related diseases.

30 years after: CNS actions of prolactin: Sources, mechanisms and physiological significance.

Our understanding of the neural actions of prolactin (PRL) and its biochemical basis has expanded greatly over the past three decades. During this time, major progress has been made, including clarification of how PRL accesses the brain, identification of the PRL receptor and the sites where it is expressed within the brain, determination of the neurochemical mechanism of action of PRL and its effect on genomic expression in neurones, identification of the neural sites where PRL acts to stimulate maternal behaviour and related affective states, and exploration of how life experiences impact neural PRL receptor activity and actions. The next 30 years promise to reveal a myriad of basic and clinical findings regarding new roles for PRL and a greater indepth understanding of how and where PRL affects physiological and behavioural processes.