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Pumped-up roosters
Neuroendocrinology at UMass
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Connie Villalba '93, '00G
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IN 1849, THE SCIENTIST ARNOLD Berthold discovered that roosters that had been castrated stopped romancing hens and skirmishing with other roosters the way their intact brethren did. He also found that implanting new testes into the bellies of castrated roosters restored their strutting, pecking ways. At the time, scientists did not know that organs other than the brain could indirectly affect behavior. So when newly implanted testes that lacked any direct connection to the brain restored the masculine antics of emasculated roosters, scientists began to wonder if organs like the testes could send messages to the brain without the need for intermediary nerves.
Berthold’s experiments, which are the first discussion point in the UMass graduate seminar, “Landmark Papers in Neuroendocrinology,” represent the birth of that field, the study of the interplay between hormones and the nervous system.
Following in Berthold’s footsteps, at least 10 UMass faculty and dozens of postdoctoral fellows, graduate students and undergraduates are busily pursuing other questions in neuroendocrinology. Psychology Professors Eric Corp and George Wade, and Veterinary and Animal Sciences Professor Deborah Good study how hormones affect appetite and body weight and, reciprocally, how food intake modifies the actions of sex hormones on the brain. Biologist Rolf Karlstrom tracks the development of “the master gland,” the pituitary, in a fish whose embryonic stages closely resemble those of humans. And, in collaboration with UMass primatologist Melinda Novak, Psychology Professor Jerrold Meyer asks whether stress hormones somehow promote self-destructive behavior in rhesus monkeys. Together, these professors and several of their colleagues comprise the UMass Center for Neuroendocrine Studies (CNS).
This center, meant to promote research and training in neuroendocrinology, was formed in 1998 under the direction of UMass Psychology Professor and alumnus (’73, ’77G) Jeffrey Blaustein. At that time, says Blaustein, “we had a number of talented neuroendocrinologists at the university, but few people knew of our strength in the field. By forming a center, we realized we could increase our visibility and possibly attract more students, post-docs and training grants.”
Just as predicted, once the UMass neuroendocrinology contingent coalesced into a center – unified by a shared objective rather than an edifice – it earned a five-year, $800,000 training grant from the National Institutes of Health, and it initiated a now nationally recognized yearly symposium. The training grant, in addition to coffering funds for the university, supports innovative research for burgeoning graduate students and worthy postdocs. The symposium, in turn, attracts hundreds of attendees from all over the Northeast and assembles presentations by luminaries in the field, such as Martha McClintock, who first discovered that women living in close proximity synchronize their menstrual cycles. What’s more, the CNS has earned recognition among outside academic institutions and national funding agencies. Indeed, most of the CNS faculty note that the formation of the center has lubricated the grant-submission process, and Geert De Vries, the current CNS director, believes his recent election as president of the prestigious Society for Behavioral Neuroendocrinology has much to do with the center’s reputation.
Still, the most important contribution of the center is not in the visibility it provides or the money it brings in, but in the exemplary research it supports.
MALES AND FEMALES:
How their Brains and Spinal Cords Differ
It was not until the 1970’s, when tensions around feminism and the equality of women were running high, that scientists first discovered that the brains of male and female animals actually look different. Soon thereafter, in 1981, De Vries – then living in his Dutch homeland – characterized the first sex difference in brain chemistry. He showed that, relative to their female counterparts, certain parts of the male rat brain produce two to three times more vasopressin (a neurotransmitter).
Having dedicated his career to understanding this discovery, De Vries has since shown that the differences in the system he studies arise because fetal and newborn male rats produce generous amounts of testosterone, a hormone now recognized as an important modifier of brain development, whereas females produce very little. But De Vries’ latest research suggests something even more exciting: that some sex differences in the brain are independent of hormones and are instead genetically determined. This, the latest of De Vries’ irreverent theories, flies in the face of conventional wisdom, which states that the brains of mammals are “female” by default, unless they receive testosterone.
In the lab adjacent to De Vries’, Nancy Forger and her charges study another aspect of the nervous system, the spinal cord. Concentrating on motoneurons, the nerve cells that control muscle movement and that might be damaged during traumatic spinal injury, Forger explores the role hormones play in keeping certain cells fat and healthy. In male rats, the motoneurons that govern movements of the penis are multiple and developed, while the corresponding neurons in female spinal cords are sparse and shrunken. Testosterone is responsible for these sex differences, and work in the Forger lab now concentrates on how testosterone might regulate the death and survival of neurons.
Hormone-driven sex differences like the ones De Vries and Forger study exist in humans, too, and they may play a role in how drugs and genetic or neurodegenerative diseases affect men and women differently. What’s more, understanding how testosterone and other hormones enhance the growth of certain types of neurons may provide insight into ways that fragile or damaged nerve cells can be protected from degeneration. Several research groups outside UMass, for example, are exploring the possibility that estrogen can prevent or reverse some of the brain damage caused by strokes, which – incidentally – often cause more profound language and movement deficits in men than they do in women.
Sex, Sex, Sex
If there is one behavior that is surely influenced by hormones, it is sex behavior. Recognizing this, Blaustein, who is also an editor for the venerable scientific journal Endocrinology, spends his time studying how hormones and other stimuli turn female rats into rodent trollops. With two well-timed sequential hormone injections – one of estrogen, the other of progesterone, Blaustein can convince spayed female rats, normally uninterested in sex, to arch their backs, raise their rumps and shift their tails to the side for easy sexual access. If he injects only estrogen but later places a male with the female, the male suitor, if given enough time, will eventually coax her into showing exactly the same cooperative behavior.
It’s not that Blaustein is particularly intrigued by small-mammal porn. He simply uses sex behavior as a model to understand how and where hormones act on the brain to affect behavior. With this knowledge, he hopes, scientists can go on to understand how hormones influence more subtle behaviors, such as spatial navigation and speech, and when and if therapeutic drugs mimic hormones.
The handful of cells in the brain that respond to progesterone in order to “turn on” female rats (and likely women) also contains receptors for dopamine, a neurotransmitter that is important in controlling movement, in conveying pleasure and in promoting aggression. Drugs used in humans to manipulate the dopamine system may therefore affect processes or behaviors normally regulated by progesterone. Indeed, Blaustein theorizes that “the side effects of many drugs may be due to their interactions with hormone-sensitive parts of the brain.”
Food and Sex
Psychology Professor George Wade, who was Blaustein’s doctoral advisor at UMass in the mid-’70s, professes interest in everything that is scientifically “counterintuitive.” He has dedicated much of his career to understanding how and why female mammals become infertile when they don’t have enough calories.
Female endurance athletes and women who are malnourished stop menstruating and lose the ability to reproduce. That part of the equation makes intuitive sense: If your body lacks the resources to sustain a pregnancy, it should avoid that energy-costly condition. But how do you (or rather your brain) gauge whether you have those resources?
“The prevailing dogma in the ’80s,” says Wade, “was that women had to maintain a minimal percentage of body fat to be fertile.” The brain would shut down reproduction, scientists believed, if it did not detect adequate fat stores. Think of rotund fertility goddesses.
Here comes Wade’s counterintuitive discovery: No matter how portly you are, if your brain doesn’t detect adequate calorie availability, it shuts down reproduction. Wade gave hamsters 2-deoxyglucose, a synthetic form of glucose that cannot be used for energy, but that looks and smells like glucose to the body’s cells. In other words, in these hamsters, he essentially induced a diabetic state. Females – even chubby ones – that had received 2-deoxyglucose would not show sex behavior when prompted with the appropriate sex hormones, he found. Since then, he’s been trying to determine the brain circuitry responsible for this phenomenon.
Environmental Contaminants and the
Brain-Hormone Connection
Rather than study how nutrition influences neuroendocrinology, UMass biologists Sandra Petersen and Thomas Zoeller study how so-called environmental endocrine disrupters affect the brain-hormone connection.
Environmental endocrine disrupters are chemical waste products that mimic or block the actions of hormones. For example, the pesticide-constituent DDT, made famous because of its deleterious effects on the eggs of bald eagles, is an endocrine disrupter. Polychlorinated biphenyls (PCBs), found in industrial solvents and other manufactured contaminants, are another potent type of endocrine disrupter.
“All humans, no matter what they eat or where they live, take in about one to two picograms of PCBs a day,” says Petersen, “and those contaminants stay in our fat for seven to 15 years.” In certain contaminant-rich areas, such as the Great Lakes region, the exposure to endocrine disrupters may be much higher. Indeed, many children born in the Great Lakes region have lower IQs and more learning disabilities than children elsewhere in the country. Petersen and Zoeller suspect that these deficits may result from disruptions of hormone-directed brain development. Consequently, they expose rat fetuses to endocrine disrupters and examine whether their brains develop differently from the brains of unexposed fetuses.
So far, Petersen has identified the specific brain cells with which one potent endocrine disrupter (called TCDD) specifically binds. Once attached to those cells, the endocrine disrupter interferes with brain-directed hormone surges that are crucial to normal reproduction in female rats. These cells, in addition to controlling aspects of reproduction, likely perform a number of other tasks, so her findings may hold universal clues to how endocrine disrupters affect the nervous system. Soon, Petersen will be collaborating with Naomi Rance at the University of Arizona Medical School in Tucson to study how her findings apply to humans.
Zoeller, in the meantime, has been exploring how endocrine disrupters interact with thyroid hormone, a hormone that typically invokes thoughts of energy and metabolism and of thyroid deficiencies among people with weight problems. But in the developing brain, thyroid hormone seems to play a much more important and little-understood role. For example, Zoeller’s work suggests that thyroid hormone directs the production of specialized nerve-supporting brain cells called glial cells.
Exposure to PCBs lowers thyroid hormone levels, so Zoeller is studying how PCBs affect processes normally controlled by thyroid function. However, the role that thyroid hormone plays in the development of the brain is still poorly understood. Consequently, last fall, with economic support from the CNS, Zoeller organized the first national scientific meeting on “Thyroid Hormone and Brain Development” at the National Institute of Environmental Health Sciences headquarters in North Carolina. “Top administrators from the Environmental Protection Agency were there, along with many clinicians,” says Zoeller. “I think it was the watershed event I hoped it would be.”
Keeping Time
In addition to environmental pollutants, the brain and body register and respond to other environmental factors, chief among them, light. Melatonin, a hormone that many have heard about in the context of jet-lag, informs the body of the time of day and the time of year. Long pulses of melatonin, for example, occur only when the days are short and the nights long; and in certain species they serve to shut down reproduction during harsh, inhospitable periods. Still, melatonin is a mere messenger for the part of the brain that tells time, the “suprachiasmatic nucleus.” In fact, the suprachiasmatic nucleus, affectionately called “the clock,” affects not only melatonin but the activity of genes throughout the body.
In an effort to understand how the clock turns genes on and off, UMass biologist Eric Bittman has been analyzing tissue samples taken from a variety of hamster organs at different times of day. He has shown that removing the clock eliminates normally present fluctuations in gene activity. And he has shown that the daily genetic ebb and flow return if you replace the hamsters’ absent clocks with donated fetal clocks.
Work like Bittman’s is forging a basic foundation on which to study rhythm dysfunction in humans, including sleep disorders and possibly seasonal affective disorder.
Endocrinology Meets Neuroscience
Looking at just about every endocrine organ, from the pineal gland to the thyroid gland to the ovaries, scientists at UMass are searching for the chemical “informants” that help the brain direct the body. After centuries of compartmentalizing science and medicine into discrete, chewable disciplines, neuroendocrinologists and researchers in similar interdisciplinary fields are realizing that science is integrative. The CNS, which represents the collaborative efforts of researchers in the Morrill Science Center, Tobin Hall (home to the psychology department), and Paige Hall, which houses the veterinary and animal sciences center, beautifully illustrates UMass’ dedication to that renaissance. |
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Pumped-up roosters
Roosters: More images
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