Hormonal signaling in the brain: radical shift in understanding information processing

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Mike Ludwig added that research in many centers has made it "apparent that hypothalamic neurons employ a vast diversity of chemical signals to communicate information, including more than 60 peptides. Many of these peptides, when released within the brain, trigger coherent, specific, complex behaviors, including sexual and social behaviors. Increasingly we are recognizing that peptide signals play a key role in information processing that is quite unlike the role played by conventional neurotransmitters."

Ludwig and Leng are scheduled to speak at the American Physiological Society's 2005 Conference, "Neurohypophyseal Hormones: From Genomics and Physiology to Disease," plus the latest developments toward clinical applications in Steamboat Springs, Colorado.

Leng and Ludwig also are scheduled to participate July 19 in the symposium, "Central release and actions of NH hormones," chaired by Quentin Pittman, University of Calgary, and Larry Young, Emory University School of Medicine.

"Melanocortin and oxytocin in facilitated sexual responses." Gareth Leng, Celine Caquineau, Nancy Sabatier, Alison Douglas, University of Edinburgh.

Leng described the now-accepted notion that "release of oxytocin and vasopressin in the brain occurs from dendrites, which are conventionally thought to be structures that receive information rather than transmit information."

Alpha-MSH: key role in sex drive - and an OT site switch

For instance, Leng described how alpha-MSH, another peptide neurohormone, can stimulate oxytocin (OT) release from dendrites while blocking "normal" OT release at the axonal release sites. "The important new experiment here," he said, "was to find a link between endogenous alpha-MSH - that is, alpha-MSH produced within the brain - sexual behavior and oxytocin." Pairing sexually experienced male rats with sexually receptive females, the researchers injected a certain receptor antagonist (MC4) and then recorded their behavior.

All the control (non-treated) rats mated very rapidly. Of the rats injected with the receptor antagonist, about one-third showed no interest in mating. The others mated, but later when compared with the controls. Laboratory tests showed that the control rats had a lot of specific protein (Fos) in magnocellular oxytocin cells, less but some Fos in the antagonist-treated rats that mated late, but none at all in the antagonist-treated rats that didn't mate.

"These experiments provide pretty strong evidence that the effects of alpha-MSH on male sexual behavior are the result of OT release from the dendrites of the magnocellular neurons," Leng stated. "More importantly to me at least, they show that inside the brain there is a system of alpha-MSH-producing neurons that plays a key role in regulating sex drive," Leng concluded. In a broader sense, he added, "it also shows that alpha-MSH can act as a kind of 'switch' to change the site of oxytocin's release, either to the brain, or to the blood where it circulates to the body's periphery."

Priming: mechanism that may "re-wire brain circuitry, and explain behavior change"

Mike Ludwig described related research at Edinburgh aimed at understanding the mechanisms involved in "priming" the release of OT and vasopressin (VP). Priming he pointed out, is a new mechanism concept "that can change the functional connectivity of neurons, in effect re-wiring circuits within the brain. Thus priming apparently has the capacity to explain changes in behavior," Ludwig asserted.

He explained that it's important to understand the "fine details of dendritic release because OT acts in the brain to arouse sexual, friendly and motherly feelings. In contrast, VP acts in the brain to increase aggressiveness and feelings of being stress. Other nerve cells release peptides in a similar way, and they have effects on other emotions and behavior. So understanding dendrites and dendritic release is an essential part of increasing our understanding of how the brain works."

Ludwig said "priming is a remarkable phenomenon with potentially profound consequences on how the brain works." He said agents that trigger dendritic OT release via mobilization of intracellular calcium stores also "prime" the readily releasable pool of OT in the dendrites, making the pool available for subsequent action-potential-dependent release.

This is important, Ludwig noted, because peptides elicit specific behaviors when released centrally (that is, in the brain). These effects can be very long lasting. Moreover, often the peptide may be important for initiating the behavior, but not important for maintaining that behavior.

The OT-VP plexus: The endocrine gland in the brain?

"We believe that the dendritic plexus of OT and VP neurons acts as an endocrine gland within the brain," Ludwig said. "When dendritic release is primed, this internal gland can sustain prolonged release of large amounts of peptide that then diffuse through the brain to reach targets at many different brain sites that express OT receptors. At these sites, we suspect OT has the same effect that it has on OT neurons. That is, we suspect it primes the releasable pools of peptides in its targets, altering the functional connectivity of the neuronal networks, of which the OT-sensitive neurons are a part," Ludwig said.

"Thus oxytocin released centrally triggers a cascade of temporary functional reorganization of specific neuronal networks, providing the substrate for prolonged behavioral effects," Ludwig concluded.

"Mechanisms underlying independent release of dendritic and neurohypophyseal oxytocin and vasopressin release." Mike Ludwig, University of Edinburgh. Funded by Wellcome Trust and BBSRC (U.K. Office of Science & Technology's Biotechnology and Biological Sciences Research Council).

The American Physiological Society