John D. Buntin - US grants

Prolactin (PRL) is a clinically important pituitary hormone and neuropeptide which has been implicated in the expression of a variety of vertebrate behavior patterns. In the vast majority of cases, however, the specificity and site(s) of PRL action, and the relationship between PRL dose and behavioral response remain unknown. Accordingly, the proposed research would characterize in detail the relationship between PRL and several different PRL-sensitive behaviors in a single species, the ring dove (Streptopelia risoria). This species is ideally suited for these studies because: 1) there is more evidence for the existence of PRL-dependent behavior patterns in the ring dove than in other vertebrates, and 2) there is evidence for both central and peripheral sites of action of PRL in promoting various behavior changes in this species. Three PRL-dependent behaviors would be explored. 1) PRL-induced ingestive behavior: The time course, dose-response properties and specificity of PRL's centrally mediated action on food and water intake would be characterized following intracerebroventricular (ICV) injection of purified ovine PRL. To provide a neuroendocrine correlate of PRL's behavioral actions, parallel studies would be conducted on PRL-induced suppression of gonadotropin secretion, which also appears to be centrally mediated. 2) PRL-induced parental behavior: The effects of ICV injections of PRL on parental behavior in non-breeding doves would be tested to determine whether the increase in parental behavior which is observed following systemic injection of the hormone is due to a direct action of PRL on the brain or to effects on peripheral target organs. 3) PRL effects on incubation behavior: A study would be conducted to determine if subcutaneous PRL injections can prevent the decline and early termination of sitting activity which normally occurs in doves which are separated from their mates during the early incubation period. Clarification of PRL's role in maintaining ongoing incubation will help to interpret previous findings that PRL maintains readiness to incubate in nest-deprived doves. Collectively, the proposed experiments would contribute significantly towards an understanding of the behavioral and neuroendocrine pathology of hyperprolactinemia in men and women and should further our knowledge of the mechanism of neuroleptic drug action. These results will also help in formulating general principles of neuropeptide and protein hormone action on behavior.

Prolactin (PRL) is a pituitary hormone and putative neuropeptide with an exceptionally diverse but poorly understood array of behavioral actions. The proposed research will employ the ring dove (Streptopelia risoria) as a model system to explore he physiological mechanisms by which PRL acts in the central nervous system (CNS) and n peripheral target tissues to influence behavioral expression and to determine where he hormone acts in the brain to promote those changes that are centrally mediated. The ring dove is well suited for these studies because 1) a variety of PRL-induced behavioral alterations have been documented in this species, 2) PRL acts at both central, and peripheral sites to evoke these various behavioral changes, and 3) the distribution of PRL-sensitive target cells has been precisely mapped in the ring dove brain. The proposed research would follow up on previous NIMH-sponsored characterization studies to accomplish five specific aims: 1) to define the role of four PRL-sensitive regions within the dove brain in promoting PRL-induced feeding behavior and suppression of gonadotropin secretion (which in turn could have behavioral consequences); 2) to more precisely define the nature of the receptor population(s) within the dove CNS which mediate PRL and growth hormone-induced changes in feeding and gonadotropin secretion by testing the degree to which these hormone actions can be mimicked or blocked by antibodies against purified PRL receptors; 3) To determine whether PRL-induced changes n gonadotropin secretion are due to altered pituitary sensitivity to gonadotropin releasing hormone (GNRH) or altered GNRH secretion; 4) to define the CNS sites of PRL action in promoting parental responsiveness towards young, the specificity of this centrally mediated action, and the role of PRL-induced changes in non-neural target tissues in promoting parental activity; 5) to determine if intracerebroventricular injections of PRL maintain ongoing incubation behavior in mate-separated doves. These studies are preparatory to a future examination of the neurochemical basis of PRL's behavioral action and the role of native dove PRL in promoting functionally significant behavioral changes in this species. Collectively, these experiments should help elucidate the physiological mechanisms underlying the behavioral and neuroendocrine pathologies associated with clinical hyperprolactinemia and will aid in the formulation of general principles underlying protein hormone-behavior interactions.

Prolactin (PRL) is a pituitary hormone and putative neuropeptide with an exceptionally diverse but poorly understood array of behavioral actions. The proposed research will employ the ring dove (Streptopelia risoria) as a model system to explore he physiological mechanisms by which PRL acts in the central nervous system (CNS) and n peripheral target tissues to influence behavioral expression and to determine where he hormone acts in the brain to promote those changes that are centrally mediated. The ring dove is well suited for these studies because 1) a variety of PRL-induced behavioral alterations have been documented in this species, 2) PRL acts at both central, and peripheral sites to evoke these various behavioral changes, and 3) the distribution of PRL-sensitive target cells has been precisely mapped in the ring dove brain. The proposed research would follow up on previous NIMH-sponsored characterization studies to accomplish five specific aims: 1) to define the role of four PRL-sensitive regions within the dove brain in promoting PRL-induced feeding behavior and suppression of gonadotropin secretion (which in turn could have behavioral consequences); 2) to more precisely define the nature of the receptor population(s) within the dove CNS which mediate PRL and growth hormone-induced changes in feeding and gonadotropin secretion by testing the degree to which these hormone actions can be mimicked or blocked by antibodies against purified PRL receptors; 3) To determine whether PRL-induced changes n gonadotropin secretion are due to altered pituitary sensitivity to gonadotropin releasing hormone (GNRH) or altered GNRH secretion; 4) to define the CNS sites of PRL action in promoting parental responsiveness towards young, the specificity of this centrally mediated action, and the role of PRL-induced changes in non-neural target tissues in promoting parental activity; 5) to determine if intracerebroventricular injections of PRL maintain ongoing incubation behavior in mate-separated doves. These studies are preparatory to a future examination of the neurochemical basis of PRL's behavioral action and the role of native dove PRL in promoting functionally significant behavioral changes in this species. Collectively, these experiments should help elucidate the physiological mechanisms underlying the behavioral and neuroendocrine pathologies associated with clinical hyperprolactinemia and will aid in the formulation of general principles underlying protein hormone-behavior interactions.

Prolactin (PRL) is a pituitary hormone and putative neuropeptide with an exceptionally diverse but poorly understood array of behavioral actions. The proposed research will employ the ring dove (Streptopelia risoria) as a model system to explore he physiological mechanisms by which PRL acts in the central nervous system (CNS) and n peripheral target tissues to influence behavioral expression and to determine where he hormone acts in the brain to promote those changes that are centrally mediated. The ring dove is well suited for these studies because 1) a variety of PRL-induced behavioral alterations have been documented in this species, 2) PRL acts at both central, and peripheral sites to evoke these various behavioral changes, and 3) the distribution of PRL-sensitive target cells has been precisely mapped in the ring dove brain. The proposed research would follow up on previous NIMH-sponsored characterization studies to accomplish five specific aims: 1) to define the role of four PRL-sensitive regions within the dove brain in promoting PRL-induced feeding behavior and suppression of gonadotropin secretion (which in turn could have behavioral consequences); 2) to more precisely define the nature of the receptor population(s) within the dove CNS which mediate PRL and growth hormone-induced changes in feeding and gonadotropin secretion by testing the degree to which these hormone actions can be mimicked or blocked by antibodies against purified PRL receptors; 3) To determine whether PRL-induced changes n gonadotropin secretion are due to altered pituitary sensitivity to gonadotropin releasing hormone (GNRH) or altered GNRH secretion; 4) to define the CNS sites of PRL action in promoting parental responsiveness towards young, the specificity of this centrally mediated action, and the role of PRL-induced changes in non-neural target tissues in promoting parental activity; 5) to determine if intracerebroventricular injections of PRL maintain ongoing incubation behavior in mate-separated doves. These studies are preparatory to a future examination of the neurochemical basis of PRL's behavioral action and the role of native dove PRL in promoting functionally significant behavioral changes in this species. Collectively, these experiments should help elucidate the physiological mechanisms underlying the behavioral and neuroendocrine pathologies associated with clinical hyperprolactinemia and will aid in the formulation of general principles underlying protein hormone-behavior interactions.

DESCRIPTION (adapted from applicant's abstract): Prolactin (PRL) promotes and coordinates the various physiological and behavioral changes that are necessary for successful parental care in vertebrates. Although the effects of PRL on peripheral target organs that serve parental functions have been studied in some depth, much less is known about how PRL acts directly or indirectly on the brain to induce parental behavior and associated neuroendocrine changes, such as reduced gonadal activity. This proposal employs a powerful avian model, the ring dove (Streptopelia risoria), to explore these effects in detail. The proposed studies build on our previous work to 1) characterize the neurochemical events that mediate these changes and 2) identify key components of the neural circuitry involved. Neurochemical investigations will evaluate neuropeptide Y (NPY) and adrenal glucocorticoids as potential mediators of PRL-induced parental hyperphagia (feeding) and gonadal suppression. These studies will examine the effects of intracerebroventricular (ICV) injections of these compounds and measure changes in NPY gene expression and protein in response to PRL or glucocorticoid injection. They will also determine if these PRL-induced changes are attenuated by blocking NPY or glucocorticoid action. Studies of possible GnRH mediation of PRL-induced gonadal suppression and dopamine involvement in PRL-induced parental hyperphagia are also proposed. Neuroanatomical investigations will use immunocytochemical detection of immediate-early gene products to identify neurons that are activated in response to ICV injection of PRL, NPY, and glucocorticoids, to visualize the pattern of neuronal activation associated with parental interactions with young, and to determine how the pattern changes in response to PRL and previous parental experience. These studies contribute to the long term objective of obtaining an integrated picture of how PRL influences brain function and behavior in a parental context. They will also increase our limited understanding of how adenohypophyseal hormones influence brain activity and provide new insights into the causes of infertility, energy balance, and behavioral alterations that are associated with hyperprolactinemia in the clinical setting.

[unreadable] DESCRIPTION (provided by applicant): The long-term goal of this research is to expand our understanding of the neuroendocrine mechanisms underlying social interactions. Parental interactions with young are particularly important components of the social behavior repertoire because they are critical for survival. However, the neural and hormonal mechanisms underlying these interactions have not been adequately described and the question of whether the neural circuitry involved in parenting is common to other social behaviors remains to be resolved. The proposed studies explore the neural mechanisms responsible for the integrative actions of prolactin (PRL) in coordinating the diverse behavioral and neuroendocrine changes that are necessary for successful parental care. The ring dove (Streptopelia risoria) is chosen as the model species for investigation because it has an unusually rich repertoire of PRL-dependent behavioral and physiological changes that support parenting. The project has four specific aims: 1) to use immunocytochemical mapping of immediate early gene products to determine if PRL, social cues, and experiential factors influence activity in neuronal circuits that underlie parental motivation and parental behavior expression; 2) to determine if PRL signaling in the brain is modulated by previous parenting experience and during physiological states associated with parenting (using real time PCR, in situ hybridization, and immunocytochemistry to measure PRL receptor expression and nuclear translocation of PRL-sensitive signaling molecules); 3) to explore the role of gonadotropin releasing hormone (GnRH) and gonadotropin inhibiting hormone (GnlH) in mediating PRL's suppressive action on gonadal activity, which may be necessary in order for other PRL-induced changes in parental responsiveness to be displayed (using real time PCR, in situ hybridization, and immunocytochemistry to measure expression in specific brain regions); 4) to determine the functional importance of PRL signaling in the brain in promoting parental behavior and gonadal axis suppression (using antisense oligonucleotide technology to knock down PRL receptor expression in dove brain). These studies will expand our understanding of neural mechanisms underlying sociality and could lead to better diagnosis and treatment of individuals at risk for social adjustment disorders. They may also shed light on the causes of infertility in nursing women with elevated PRL secretion and in men and women with PRL-secreting pituitary tumors. [unreadable] [unreadable] [unreadable]