Psychoneuroendocrinology,Vol. 17, No. 4, pp. 279-282, Prinl~l in Great Britain
1992 ©1992 Pergamon Press Ltd.
EDITORIAL
PSYCHONEUROENDOCRINOLOGY OF AGING: THE BRAIN AS TARGET O R G A N OF H O R M O N E S Through both structural and functional connections, there are close interactions between the central nervous system (CNS) and the endocrine glands. During physiological aging of the brain, and even more so during pathological aging, neuron degeneration progressively occurs, along with glial proliferation, and CNS neurotransmitter systems undergo quantitative and/or qualitative dysregulation. Modifications in patterns of neuroendocrine function can result, which may serve as a biological marker of CNS impairment (Valenti, 1988). This sequence also can occur in the opposite direction. Hypothalamic peptides, pituitary hormones and the secretions of peripheral endocrine glands can affect the brain from both an anatomical and a functional standpoint. Knowledge of this latter approach is not new; its roots are in clinical findings presented in the medical literature for many years. Indeed, in several endocrine diseases certain psychopathological symptoms are frequently described: hypersomnia and decreased libido in acromegaly; anxiety, panic symptoms, irritability, and restlessness in hyperthyroidism; depression and cognitive deficits in hypothyroidism; euphoria and psychosis during chronic glucocorticoid treatment; depression in Cushing's syndrome as well as in Addison's disease; and decreased libido in hyperprolactinemic syndromes in both sexes (Brown, 1980; Leigh & Kramer, 1984; Rubin & King, 1993). Mechanisms o f Hormone Action Some hormones can affect brain function indirectly, through the mediation of metabolic changes. For example, insulin can affect brain activity and behavior by causing a rapid and marked decrease in plasma glucose concentrations, and parathyroid hormone and calcitonin can induce behavioral changes by modifying serum calcium concentrations. There also are direct actions of hormones on the brain. These can be divided into organizational and activational effects. Organizational effects are permanent and are promoted by the presence or absence of a hormone during certain developmental periods that involve structural changes of neurons and their connections. For example, sex steroid hormone influences in the prenatal and early postnatal periods (depending on the species) can permanently affect sexual behavior, in both males and females. Similarly, an early deficit in thyroid hormones can result in a lifelong reduction in cognitive performance. In contrast, activational effects of hormones are those that occur after brain development is complete; they can temporarily affect both the form and the intensity of behavioral and physiological responses (Cooper et al., 1986; Vom Saal & Finch, 1988). In recent years, many experimental studies have focused on the mechanism(s) by which hormones can directly affect the CNS. There are at least three different ways:
1. Hormones as Neurotransmitters This is the postulated typical mechanism for hypothalamic peptides. According to this hypothesis, the peptides link to specific stimulating or inhibiting neural membrane receptors (Fig. 1). Through the mediation of coupling proteins (G proteins), the enzyme adenylate cyclase can be modulated, and, as a consequence, the conversion of ATP to cAMP. cAMP, as a second messenger, through the mediation of a regulatory subunit, in turn activates the enzyme protein kinase A, which plays a central role in protein phosphorylation. In parallel, also through the mediation of G proteins, hormones can exert their biological effects by activating the membrane enzyme phospholipase C, which in turn is able to catalyze the production of inositol triphosphate (IP3) and diacylglycerol (DG) from phosphatidylinositolbiphosphate (PIP2). IP3 and DG can serve as second messengers: IP3 releases calcium from endothelial reticulum, which in turn can activate a calmodulin-dependent protein kinase, and DG directly activates the protein kinase. The final common pathway is increased protein phosphorylation. Of these two mechanisms, the one using cAMP and 279
280
G. VALENTI
PIP2
I HORMONE ASANEUROTRANSMITTER 1 ATP
[ sRo%%~W °R~I
PROTEIN PHOSPHORILATION
q
PROTEIN
FIG. 1: Schematic representation of the neurotransmitter mechanism of action of hormones on the CNS.
the other using IP3 and DG as second messengers, the latter seems to be the more likely explanation for the biological effects of hypothalamic peptides on neuronal cells. 2. Hormones as Neuromodulators Hypothalamic peptides, pituitary hormones, and peripheral endocrine gland secretions can exert their biological activity at a neuronal level by modulating neurotransmission at different targets (Fig. 2): during intraneuronal synthesis or storage of neurotransmitter molecules; during presynaptic receptor activation, with hormones modulating the negative feedback of neurotransmitters on their own synthesis; during enzymatic inactivation of the neurotransmitters in the extracellular space; and during uptake of neurotransmitters into the presynaptic neuron. Hormones also can affect postsynaptic receptor availability, modifying both their concentration and their binding capacity. Hormones such as steroids, insulin, and thyroxine are able to directly modify neuronal membrane composition, affecting the cholesterol/phospholipid ratio and consequently membrane microviscosity and receptor availability. And, by modulating the expression of the genome, hormones can activate protein synthesis, leading to increased receptor concentrations in the neuronal membrane.
INA~VA~"~ON~I PRECURSOR~~
I NE~°~°~°~T'°R1 FIG. 2: Schematic representation of the neuromodulator mechanism of action of hormones on the CNS.
3. Hormones as Neurotrophic Substances In vitro studies with neuron cultures from the cerebral cortex and the alpha motor region of experimental animals have extensively demonstrated the neurotrophic properties of several hormones, including those of
EDITORIAL
I
HORMONEASA NEUROTROPHIC AC~VATOR
HYPOTHALAMIC ~ PEPTIDES
REGENERATIVE ACTION
CELL SURVIVAL ACTH/MSH AXON ~'-.II~OUTGROWTI ENERGY GENERA~ON
PROTEIN BIOSYNTHESIS
GENETIC APPARATUS
SEX STEROIDS THYROID HORMONES INSULIN
FIG. 3: Schematic representation of the neurotrophic activator mechanism of action of hormones on the CNS.
281 the hypothalamus, the pituitary, and the peripheral endocrine glands (Fig. 3). For example, TRH induces cholineacetyltransferase activity and increases the uptake of aspartate in cultured neuronal cells, which correlate closely with cell maturation (Askanas et al., 1989; Nicoletti & Canonico, 1989). ACTH and MSH-like peptides promote cell survival and axon outgrowth when added to explanted cerebral cortex and alpham o t o r area neurons, d e m o n s t r a t i n g their involvement in the control of neural plasticity in the CNS. The neurotrophic influence of pituitary h o r m o n e s on the peripheral nervous system, on the basis of enhanced outgrowth of newly formed sprouts, also has been demonstrated (de Wied, 1988). And, sex steroids, thyroid hormones, and insulin appear to have neurotrophic activity in the CNS: Via activation of the genetic apparatus they can influence protein synthesis and energy processes in the axoplasmic transport mechanism, which plays a primary role in the maintenance of neuronal structure and function (Frolkis et al., 1990). Neurotrophic activity seems to be the primary mechanism by which organizational effects of hormones on the brain are realized.
Activational Effects of Hormones The activational effects of hormones appear to occur primarily through neurotransmitter and neuromodulator mechanisms. Hormones can exert some effects on the CNS that are dissociated from their endocrine effects. For example, the behavioral effect of the hypothalamic peptide LHRH can be dissociated from its endocrine action: In ovariectomized, estrogen-primed female rats, whether or not they had been hypophysectomized, LHRH treatment was able to stimulate mating behavior. The infusion of LHRH antiserum or an LHRH antagonist into the third ventricle of ovariectomized female rats primed with estrogen and progesterone significantly decreased mating behavior, providing further evidence for a specific behavioral effect of LHRH (Nemeroff et al., 1984). Nevertheless, under normal physiological conditions the behavioral and endocrine effects of hormones are usually not separate: The "principle of harmony" states that the secretions of a particular neuroendocrine axis produce behavioral effects consistent with their endocrine actions. For example, in the intact organism, LHRH activates gonadotropin secretion and stimulates sexual behavior; both effects are directed toward enhancing reproductive function (Nemeroff & Prange, 1978). Aging of the Human Brain The main neurological changes in aged humans involve somatosensitivity: decreased efficiency of the special senses and their integration within the CNS. Cellular and synaptic alterations underlie these progressive neurological impairments. At the cellular level, degenerative alterations of both dendrites and neuronal cell bodies, disappearance of neurons, and proliferation of astroglial cells are the most frequent findings. At the synaptic level, the aged brain presents a reduction in almost every transmitter system and at almost every step in the chemical transmission process. Changes in neuronal biosynthetic capabilities for messenger and receptor molecules, along with a failure to integrate neuronal and hormonal signals, can explain the impairment in most synaptic mechanisms. There frequently is little correlation between neuropathological findings and functional deficits in aged subjects. Two hypotheses have been advanced to explain this phenomenon. The first maintains that the physiological reshaping of brain circuits may lead to "wrong" readjustments of neural networks. According to the second hypothesis, the lack of correlation is due to the impairment of restricted neuronal populations ("pacemaker and
282
G. VALENT|
command neurons") which play a special role in the hierarchical organization of the CNS (Roberts, 1974; Agnati et al., 1990). With this background, it is not difficult to contemplate the importance of the role of hormones in both the cellular and the synaptic alterations that occur in the aging brain. Therefore, the goal of this workshop was to focus on the actual and potential capabilities of the hypothalamic peptides, the pituitary hormones, and the secretions of the peripheral endocrine glands to influence the trophism of cells and the neurotransmission and neuromodulation processes that occur in the CNS during aging. Giorgio Valenti Chair of Geriatrics University of Parma REFERENCES Agnati LF, Zoli M, Grimaldi R, Fuxe K, Toffano G, Zini I (1990) Cellular and synaptic alterations in the aging brain. Aging 2: 5-25. Askanas V, Engel NK, Eagleson K, Micaglio G (1989) Influence of TRH analogues RGH-2202 and DN-1417 on cultured ventral spinal cord neurons. Ann NY Acad Sci 533: 325-336. Brown GM (1980) Psychiatric and neurologic aspects of endocrine disease. In: Krieger DT, Hughes JC (Eds) Neuroendocrinology. Sinauer, Sunderland MA, pp 185-193. Cooper RL, Goldman LM, Rehnber GL (1986) Neuroendocrine control of reproductive function in the aging female rodent. JAGS 34: 735-751. De Wied D (1988) ACTH/MSH neuropeptides, behavior and aging. In: Valenti G (Ed) Psychoneuroendocrinology of Aging: Basic and Clinical Aspects. Liviana Press, Padova, pp 151-160. Frolkis VV, Tanin SA, Marcinko VI, Muradian KK (1990) Effects of hormones on the fast axoplasmic transport of substances in central horns of the spinal cord in rats of different ages. Arch Geront Geriatr 11: 33-41. Leigh H, Kramer SI (1984) The psychiatric manifestations of endocrine disease. Adv Intern Med 29: 413-445. Nemeroff CB, Prange AJ Jr (1978) Peptides and psychoneuroendocrinology: a perspective. Arch Gen Psychiatry 35: 999-1010. Nemeroff CB, Bissette G, Manberg PJ, Luttinger D, Prange AJ Jr (1984) Effects of hypothalamic peptides on the central nervous system. In: Nemeroff CB, Dunn AJ (Eds) Peptides, Hormones and Behavior. Spectrum, New York, pp 217-272. Nicoletti F, Canonico PL (1989) Meccanismi molecolari di plasticita neuronale. In: Scapagnini U (Ed) Psiconeuroendocrinoimmunologia. Liviana Editrice, Padova, pp 15-110. Roberts E (1974) A model of the vertebrate neuron system based largely on disinhibition: a key role for the GABA system. In: Myers RD, Raul R (Eds) Neurohumoral Coding of Brain Function. Plenum Press, New York, pp 419-448. Rubin RT, King BH (1993) Endocrine and metabolic disorders. In: Kaplan HI, Sadock BJ (Eds) Comprehensive Textbook of Psychiatry, Sixth Edition. Williams and Wilkins, Baltimore, in press. Valenti G (1988) Psychoneuroendocrinology of Aging: Basic and Clinical Aspects. Liviana Press, Padova. Vom Saal FS, Finch CE (1988) Reproductive senescence: phenomena and mechanisms in mammals and selected vertebrates. In: Knobil E, Neill J (Eds) The Physiology of Reproduction. Raven Press, New York pp 2351-2412.
1992 ©1992 Pergamon Press Ltd.
EDITORIAL
PSYCHONEUROENDOCRINOLOGY OF AGING: THE BRAIN AS TARGET O R G A N OF H O R M O N E S Through both structural and functional connections, there are close interactions between the central nervous system (CNS) and the endocrine glands. During physiological aging of the brain, and even more so during pathological aging, neuron degeneration progressively occurs, along with glial proliferation, and CNS neurotransmitter systems undergo quantitative and/or qualitative dysregulation. Modifications in patterns of neuroendocrine function can result, which may serve as a biological marker of CNS impairment (Valenti, 1988). This sequence also can occur in the opposite direction. Hypothalamic peptides, pituitary hormones and the secretions of peripheral endocrine glands can affect the brain from both an anatomical and a functional standpoint. Knowledge of this latter approach is not new; its roots are in clinical findings presented in the medical literature for many years. Indeed, in several endocrine diseases certain psychopathological symptoms are frequently described: hypersomnia and decreased libido in acromegaly; anxiety, panic symptoms, irritability, and restlessness in hyperthyroidism; depression and cognitive deficits in hypothyroidism; euphoria and psychosis during chronic glucocorticoid treatment; depression in Cushing's syndrome as well as in Addison's disease; and decreased libido in hyperprolactinemic syndromes in both sexes (Brown, 1980; Leigh & Kramer, 1984; Rubin & King, 1993). Mechanisms o f Hormone Action Some hormones can affect brain function indirectly, through the mediation of metabolic changes. For example, insulin can affect brain activity and behavior by causing a rapid and marked decrease in plasma glucose concentrations, and parathyroid hormone and calcitonin can induce behavioral changes by modifying serum calcium concentrations. There also are direct actions of hormones on the brain. These can be divided into organizational and activational effects. Organizational effects are permanent and are promoted by the presence or absence of a hormone during certain developmental periods that involve structural changes of neurons and their connections. For example, sex steroid hormone influences in the prenatal and early postnatal periods (depending on the species) can permanently affect sexual behavior, in both males and females. Similarly, an early deficit in thyroid hormones can result in a lifelong reduction in cognitive performance. In contrast, activational effects of hormones are those that occur after brain development is complete; they can temporarily affect both the form and the intensity of behavioral and physiological responses (Cooper et al., 1986; Vom Saal & Finch, 1988). In recent years, many experimental studies have focused on the mechanism(s) by which hormones can directly affect the CNS. There are at least three different ways:
1. Hormones as Neurotransmitters This is the postulated typical mechanism for hypothalamic peptides. According to this hypothesis, the peptides link to specific stimulating or inhibiting neural membrane receptors (Fig. 1). Through the mediation of coupling proteins (G proteins), the enzyme adenylate cyclase can be modulated, and, as a consequence, the conversion of ATP to cAMP. cAMP, as a second messenger, through the mediation of a regulatory subunit, in turn activates the enzyme protein kinase A, which plays a central role in protein phosphorylation. In parallel, also through the mediation of G proteins, hormones can exert their biological effects by activating the membrane enzyme phospholipase C, which in turn is able to catalyze the production of inositol triphosphate (IP3) and diacylglycerol (DG) from phosphatidylinositolbiphosphate (PIP2). IP3 and DG can serve as second messengers: IP3 releases calcium from endothelial reticulum, which in turn can activate a calmodulin-dependent protein kinase, and DG directly activates the protein kinase. The final common pathway is increased protein phosphorylation. Of these two mechanisms, the one using cAMP and 279
280
G. VALENTI
PIP2
I HORMONE ASANEUROTRANSMITTER 1 ATP
[ sRo%%~W °R~I
PROTEIN PHOSPHORILATION
q
PROTEIN
FIG. 1: Schematic representation of the neurotransmitter mechanism of action of hormones on the CNS.
the other using IP3 and DG as second messengers, the latter seems to be the more likely explanation for the biological effects of hypothalamic peptides on neuronal cells. 2. Hormones as Neuromodulators Hypothalamic peptides, pituitary hormones, and peripheral endocrine gland secretions can exert their biological activity at a neuronal level by modulating neurotransmission at different targets (Fig. 2): during intraneuronal synthesis or storage of neurotransmitter molecules; during presynaptic receptor activation, with hormones modulating the negative feedback of neurotransmitters on their own synthesis; during enzymatic inactivation of the neurotransmitters in the extracellular space; and during uptake of neurotransmitters into the presynaptic neuron. Hormones also can affect postsynaptic receptor availability, modifying both their concentration and their binding capacity. Hormones such as steroids, insulin, and thyroxine are able to directly modify neuronal membrane composition, affecting the cholesterol/phospholipid ratio and consequently membrane microviscosity and receptor availability. And, by modulating the expression of the genome, hormones can activate protein synthesis, leading to increased receptor concentrations in the neuronal membrane.
INA~VA~"~ON~I PRECURSOR~~
I NE~°~°~°~T'°R1 FIG. 2: Schematic representation of the neuromodulator mechanism of action of hormones on the CNS.
3. Hormones as Neurotrophic Substances In vitro studies with neuron cultures from the cerebral cortex and the alpha motor region of experimental animals have extensively demonstrated the neurotrophic properties of several hormones, including those of
EDITORIAL
I
HORMONEASA NEUROTROPHIC AC~VATOR
HYPOTHALAMIC ~ PEPTIDES
REGENERATIVE ACTION
CELL SURVIVAL ACTH/MSH AXON ~'-.II~OUTGROWTI ENERGY GENERA~ON
PROTEIN BIOSYNTHESIS
GENETIC APPARATUS
SEX STEROIDS THYROID HORMONES INSULIN
FIG. 3: Schematic representation of the neurotrophic activator mechanism of action of hormones on the CNS.
281 the hypothalamus, the pituitary, and the peripheral endocrine glands (Fig. 3). For example, TRH induces cholineacetyltransferase activity and increases the uptake of aspartate in cultured neuronal cells, which correlate closely with cell maturation (Askanas et al., 1989; Nicoletti & Canonico, 1989). ACTH and MSH-like peptides promote cell survival and axon outgrowth when added to explanted cerebral cortex and alpham o t o r area neurons, d e m o n s t r a t i n g their involvement in the control of neural plasticity in the CNS. The neurotrophic influence of pituitary h o r m o n e s on the peripheral nervous system, on the basis of enhanced outgrowth of newly formed sprouts, also has been demonstrated (de Wied, 1988). And, sex steroids, thyroid hormones, and insulin appear to have neurotrophic activity in the CNS: Via activation of the genetic apparatus they can influence protein synthesis and energy processes in the axoplasmic transport mechanism, which plays a primary role in the maintenance of neuronal structure and function (Frolkis et al., 1990). Neurotrophic activity seems to be the primary mechanism by which organizational effects of hormones on the brain are realized.
Activational Effects of Hormones The activational effects of hormones appear to occur primarily through neurotransmitter and neuromodulator mechanisms. Hormones can exert some effects on the CNS that are dissociated from their endocrine effects. For example, the behavioral effect of the hypothalamic peptide LHRH can be dissociated from its endocrine action: In ovariectomized, estrogen-primed female rats, whether or not they had been hypophysectomized, LHRH treatment was able to stimulate mating behavior. The infusion of LHRH antiserum or an LHRH antagonist into the third ventricle of ovariectomized female rats primed with estrogen and progesterone significantly decreased mating behavior, providing further evidence for a specific behavioral effect of LHRH (Nemeroff et al., 1984). Nevertheless, under normal physiological conditions the behavioral and endocrine effects of hormones are usually not separate: The "principle of harmony" states that the secretions of a particular neuroendocrine axis produce behavioral effects consistent with their endocrine actions. For example, in the intact organism, LHRH activates gonadotropin secretion and stimulates sexual behavior; both effects are directed toward enhancing reproductive function (Nemeroff & Prange, 1978). Aging of the Human Brain The main neurological changes in aged humans involve somatosensitivity: decreased efficiency of the special senses and their integration within the CNS. Cellular and synaptic alterations underlie these progressive neurological impairments. At the cellular level, degenerative alterations of both dendrites and neuronal cell bodies, disappearance of neurons, and proliferation of astroglial cells are the most frequent findings. At the synaptic level, the aged brain presents a reduction in almost every transmitter system and at almost every step in the chemical transmission process. Changes in neuronal biosynthetic capabilities for messenger and receptor molecules, along with a failure to integrate neuronal and hormonal signals, can explain the impairment in most synaptic mechanisms. There frequently is little correlation between neuropathological findings and functional deficits in aged subjects. Two hypotheses have been advanced to explain this phenomenon. The first maintains that the physiological reshaping of brain circuits may lead to "wrong" readjustments of neural networks. According to the second hypothesis, the lack of correlation is due to the impairment of restricted neuronal populations ("pacemaker and
282
G. VALENT|
command neurons") which play a special role in the hierarchical organization of the CNS (Roberts, 1974; Agnati et al., 1990). With this background, it is not difficult to contemplate the importance of the role of hormones in both the cellular and the synaptic alterations that occur in the aging brain. Therefore, the goal of this workshop was to focus on the actual and potential capabilities of the hypothalamic peptides, the pituitary hormones, and the secretions of the peripheral endocrine glands to influence the trophism of cells and the neurotransmission and neuromodulation processes that occur in the CNS during aging. Giorgio Valenti Chair of Geriatrics University of Parma REFERENCES Agnati LF, Zoli M, Grimaldi R, Fuxe K, Toffano G, Zini I (1990) Cellular and synaptic alterations in the aging brain. Aging 2: 5-25. Askanas V, Engel NK, Eagleson K, Micaglio G (1989) Influence of TRH analogues RGH-2202 and DN-1417 on cultured ventral spinal cord neurons. Ann NY Acad Sci 533: 325-336. Brown GM (1980) Psychiatric and neurologic aspects of endocrine disease. In: Krieger DT, Hughes JC (Eds) Neuroendocrinology. Sinauer, Sunderland MA, pp 185-193. Cooper RL, Goldman LM, Rehnber GL (1986) Neuroendocrine control of reproductive function in the aging female rodent. JAGS 34: 735-751. De Wied D (1988) ACTH/MSH neuropeptides, behavior and aging. In: Valenti G (Ed) Psychoneuroendocrinology of Aging: Basic and Clinical Aspects. Liviana Press, Padova, pp 151-160. Frolkis VV, Tanin SA, Marcinko VI, Muradian KK (1990) Effects of hormones on the fast axoplasmic transport of substances in central horns of the spinal cord in rats of different ages. Arch Geront Geriatr 11: 33-41. Leigh H, Kramer SI (1984) The psychiatric manifestations of endocrine disease. Adv Intern Med 29: 413-445. Nemeroff CB, Prange AJ Jr (1978) Peptides and psychoneuroendocrinology: a perspective. Arch Gen Psychiatry 35: 999-1010. Nemeroff CB, Bissette G, Manberg PJ, Luttinger D, Prange AJ Jr (1984) Effects of hypothalamic peptides on the central nervous system. In: Nemeroff CB, Dunn AJ (Eds) Peptides, Hormones and Behavior. Spectrum, New York, pp 217-272. Nicoletti F, Canonico PL (1989) Meccanismi molecolari di plasticita neuronale. In: Scapagnini U (Ed) Psiconeuroendocrinoimmunologia. Liviana Editrice, Padova, pp 15-110. Roberts E (1974) A model of the vertebrate neuron system based largely on disinhibition: a key role for the GABA system. In: Myers RD, Raul R (Eds) Neurohumoral Coding of Brain Function. Plenum Press, New York, pp 419-448. Rubin RT, King BH (1993) Endocrine and metabolic disorders. In: Kaplan HI, Sadock BJ (Eds) Comprehensive Textbook of Psychiatry, Sixth Edition. Williams and Wilkins, Baltimore, in press. Valenti G (1988) Psychoneuroendocrinology of Aging: Basic and Clinical Aspects. Liviana Press, Padova. Vom Saal FS, Finch CE (1988) Reproductive senescence: phenomena and mechanisms in mammals and selected vertebrates. In: Knobil E, Neill J (Eds) The Physiology of Reproduction. Raven Press, New York pp 2351-2412.
