Responsiveness to estradiol in central nervous system of aging female rats

The age related decline in reproductive capacity in the female rat is examined in terms of physiological and behavioral changes in responsiveness to estradiol evidenced during the second year of life. After 9–12 months of age, regular estrous cycles are replaced by constant estrous, prolonged pseudopregnancy, or anestrous states, with concurrent alterations in endocrine function. Some of the mechanisms implicated in the mediation of these changes are reviewed. Estrogenic influences on estrous behavior and the control of feeding and body weight in aged rats, as well as the effects of parity on aged endocrinological functioning are discussed.     

Analysis of the ontogeny of galanin in the rat central nervous system by immunohistochemistry and radioimmunoassay

The development of galanin-like immunoreactivity in the rat central nervous system has been investigated immunologically. Galanin-positive processes in the central nervous system were first recognized at day 1 post-natal, in the dorsal horn of the spinal cord. At day 2, the first galanin-immunoreactive neuronal somata were visualized in several regions of the diencephalon; at later stages of maturation positive cells were also detected in many brain stem areas. The number, density and staining intensity of galanin-positive structures in these and other regions increased steadily until day 28, by which age the adult disposition was attained. Increases in the concentrations of galanin-like immunoreactivity during maturation of the animals closely paralleled the immunohistochemical findings. No reduction in galanin-like immunoreactivity was noted in any area during later post-natal ages. The present study indicates that the ontogeny of galanin-like immunoreactivity in the rat central nervous system occurs entirely post-natally. The developmental profile is consistent with the role of galanin as a putative neurotransmitter/neuromodulator in the rat brain and spinal cord.     

Interface of physical and emotional stress regulation through the endogenous opioid system and mu-opioid receptors

Unraveling the pathways and neurobiological mechanisms that underlie the regulation of physical and emotional stress responses in humans is of critical importance to understand vulnerability and resiliency factors to the development of a number of complex physical and psychopathological states. Dysregulation of central stress response circuits have been implicated in the establishment of conditions as diverse as persistent pain, mood and personality disorders and substance abuse and dependence. The present review examines the contribution of the endogenous opioid system and μ-opioid receptors to the modulation and adaptation of the organism to challenges, such as sustained pain and negative emotional states, which threaten its internal homeostasis. Data accumulated in animal models, and more recently in humans, point to this neurotransmitter system as a critical modulator of the transition from acute (warning signals) to sustained (stressor) environmental adversity. The existence of pathways and regulatory mechanisms common to the regulation of both physical and emotional states transcend classical categorical disease classifications, and point to the need to utilize dimensional, “symptom”-related approximations to their study. Possible future areas of study at the interface of “mind” (cognitive–emotional) and “body” (physical) functions are delineated in this context.     

Somatic sensory transmission to the cortex during movement: Gating of single cell responses to touch

We recently showed that the responsiveness of single somatosensory (SI) cortical units in rats to electrical stimulation of cutaneous receptive field areas was markedly decreased during motor behaviors. The present study was conducted to determine if the responses of such cells to natural touch stimulation occurring as a result of movement were also suppressed relative to their responses to passive touch of the same area. We recorded cells in the forepaw area of the SI cortex of awake, freely moving rats. Perievent histograms of the units' sensory responses to passive touch stimulation of the palmar skin area with a flat probe were compared with histograms of the responses of the same cells to contact of the same paw on the ground during running. Thirty-two of 61 cells responded similarly to both “active” and “passive” touch. Twenty-nine of the 61 SI cells, however, responded only weakly or not at all to foot contact during forced treadmill locomotion. Thorough analysis of the nature of the receptive fields of those cells indicated that their lack of response to footfall could not be explained by simple differences in the passive skin stimulation and thus may have been caused by a suppression of sensory transmission without the central nervous system. Most cells which did not respond to footfall in “regular” locomotion did respond to contacts of the foot on various surfaces during certain types of “irregular” locomotor behaviors, especially those in which the paw was used to explore the environment. These data suggest that, during movements in which the paw touches various objects, transmission of the resulting sensory input to various cortical cells may depend on the motor or behavioral context in which the movements are made.     

Ontogeny of (−)-[H]norepinephrine uptake properties of synaptic storage vesicles of rat brain

The ontogeny of[3H]norepinephrine uptake mechanisms has been examined in synaptosomes and storage vesicles isolated from rat whole brain. The [3H]norepinephrine accumulated by synaptosomes was low in neonates, but reached adult levels by 15 days of age. In contrast, development of[3H]norepinephrine uptake into isolated rat brain storage vesicles was not complete until 38 days of age. Kinetic analysis of the developing vesicular uptake mechanism revealed no change in Km, while maximal uptake increased progressively from birth to maturity. Storage vesicles from immature and adult rats exhibited similar energy requirements for uptake as determined by their dependence on ATP-Mg2+ concentration; furthermore, the degree of inhibition of [3H]norepinephrine uptake by other amines was the same in both vesicle preparations. Thus, storage vesicles isolated from adult and developing rats display an in vitro[3H]norepinephrine uptake mechanism with properties that are kinetically and pharmacologically similar. The results suggest that, while the number of storage vesicles in the central nervous system increases during development, those vesicles that are present possess a fully functional amine uptake system.     

Signal transduction for clinicians: why should we care?

Neurons must respond to a bewildering array of external and internal stimuli and must distinguish among them to generate an appropriate response or change in metabolic or electrical activity. Furthermore, the response of a cell to a given stimulus must depend on what else is happening inside and outside the cell at the time of arrival of that stimulus. The process of signal transduction is what gives the cell and organism the flexibility and “knowledge base” to carry out these functions. Conversely, aberrations of signal transduction underlie an increasing array of developmental, genetic, and acquired diseases and conditions of the nervous system. Pharmacological modulation of signal transduction pathways and their effectors holds great promise for the remediation of these neurologic disorders.     

Variations in the activity and sexual dimorphism of hippocampal pyramidal neurons during the postnatal development of the rat

The CA 1 pyramidal neurons of the dorsal and ventral hippocampus as also the neurons of the granular layer of the parietal cortex, which were investigated in comparison, show karyovolumetrically revealed significant variations of their activities during the postnatal development of the rat (between the 5th and 60th postnatal day). These variations represent the total expression of the gene activities related to the development and differentiation as also to the synchronously requested specific performances of the neurons for the organism. They are characterized by a more or less distinct regional specificity as also a sexual dimorphism--especially distinct during the first 3...4 weeks of postnatal development--beside several distinct principal coincidences. Characteristic are the peaks of activity at the 10th and 20th day of postnatal life and additionally at the 45th day in male animals. The activation of the hippocampal pyramidal neurons as also of the neurons in the granular layer of the parietal cortex from day 5 to day 10 of the postnatal development, which comes to appearance as an increase of cell nuclear volume between 35,2 and 142,5 per cent, coincides with the growing period of the central nervous system, which lasts in the rat till the 10th postnatal day, and with the postnatal initial phase of several extracerebral developmental, differentiation and maturation processes. The variations of neuronal activities occurring after the 10th day and ceasing in the 4th week of the postnatal development coincide with the maturation period of the central nervous system and of the extracerebral systems. The peak of activity appearing around the 45th day of life in male rats seems to be related to the puberty. The sexual dimorphism of the hippocampal pyramidal neurons as also of the neurons in the granular layer of the parietal cortex, realized in the cell nuclear volume resp. neuronal activity, is apparently the reflection of the sexual specific differentiation of the central nervous system and is a partial phenomenon of the complex dimorphism of the both sexes. It shows also a regional specific character.     

Ontogeny of vasoactive intestinal peptide and somatostatin in different structures of the rat brain: effects of hypo- and hypercorticism

The ontogeny of the vasoactive intestinal peptide (VIP) and somatostatin (SRIF) was studied in various structures of the rat central nervous system (CNS), using specific radioimmunoassays. The effect of adrenal corticoids on the concentration of both peptides was investigated during the development of the rat from 3 days before birth to 2 months after birth. The evolution of both peptides was different since SRIF was found before birth in each structure tested while VIP appeared only after birth in the same structures. However, after birth the ontogeny of VIP and SRIF was quite similar and the maximum concentration of both peptides occurred between day 14 and day 21. Hypercorticism (implant of corticosterone) and hypocorticism (Metyrapone injections) modified the postnatal evolution of both peptides, suggesting that corticoids play an important role in the brain developmental patterns of VIP and SRIF.     

Expression and localization of the fibronectin receptor in the mouse nervous system

Cell surface receptors for extracellular matrix components have recently been characterized as integral membrane complexes with common features in their structural and functional properties. We have investigated the expression of the mammalian fibronectin receptor in the mouse nervous system using immunocytological and immunochemical methods. The fibronectin receptor was detectable on immature oligodendrocytes and immature and mature astrocytes in culture, while central nervous system neurons did not reveal detectable levels of fibronectin receptor at the developmental stages studied. In the peripheral nervous system both glia and neurons were found to express the fibronectin receptor. The receptor complex in both peripheral and central nervous system has an apparent molecular weight of approximately 140 kD under reducing conditions and resolves into two or three distinct protein bands under nonreducing conditions. The fibronectin receptor expresses the L2/HNK-1 epitope that is characteristic of several adhesion molecules, including L1, N-CAM, the myelin-associated glycoprotein, and J1 and thus is another member of the L2/HNK-1 family of adhesion molecules. The L2/HNK-1 carbohydrate epitope is expressed differently and independently of the fibronectin receptor protein backbone in that it is detectable in neonatal brain but not in adult brain. Our observations attribute a functional role to the fibronectin receptor and its L2/HNK-1 carbohydrate epitope during development and maintenance of cell interactions in the central and peripheral nervous systems.     

A developmental marker of central nervous system maturation: Part II

Computer technology facilitates simultaneous comparison of changes among various neurophysiologic measures. Evaluating relationships among various sleep events provides information concerning normal central nervous system development, as well as perturbations in the electroencephalographic rhythms that accompany pathologic conditions in the neonate. Prognostic information may be derived from the “recovery” pattern of the abnormal electroencephalogram after acute neonatal illness.     

Sex steroids and connectivity in the human brain: a review of neuroimaging studies

Our brain operates by the way of interconnected networks. Connections between brain regions have been extensively studied at a functional and structural level, and impaired connectivity has been postulated as an important pathophysiological mechanism underlying several neuropsychiatric disorders. Yet the neurobiological mechanisms contributing to the development of functional and structural brain connections remain to be poorly understood. Interestingly, animal research has convincingly shown that sex steroid hormones (estrogens, progesterone and testosterone) are critically involved in myelination, forming the basis of white matter connectivity in the central nervous system. To get insights, we reviewed studies into the relation between sex steroid hormones, white matter and functional connectivity in the human brain, measured with neuroimaging. Results suggest that sex hormones organize structural connections, and activate the brain areas they connect. These processes could underlie a better integration of structural and functional communication between brain regions with age. Specifically, ovarian hormones (estradiol and progesterone) may enhance both cortico-cortical and subcortico-cortical functional connectivity, whereas androgens (testosterone) may decrease subcortico-cortical functional connectivity but increase functional connectivity between subcortical brain areas. Therefore, when examining healthy brain development and aging or when investigating possible biological mechanisms of 'brain connectivity' diseases, the contribution of sex steroids should not be ignored.     

Development of spontaneous and glutamate-evoked activity is altered by chronic ethanol in cultured cerebellar Purkinje neurons

The effects of continuous exposure to ethanol on the cytological and physiological development of a central nervous system (CNS) neuron were studied using the cultured Purkinje neuron of the rat cerebellar cortex. Purkinje neurons in fetal rat brain cultures which are established at one day before birth show development comparable to that described in vivo in other studies. In culture, Purkinje neurons progress from immature rounded cells with fine neurites to mature neurons with a branched dendritic structure. These structural changes are accompanied by an increase in the duration and complexity of the excitatory response to glutamate, by transitions in the patterns of spontaneous activity, and by an increase in mean firing rate. Our results demonstrate that chronic exposure to a low concentration of ethanol (90 mg%; 19.5 mM) during development selectively alters the electrophysiological but not the morphological properties of Purkinje neurons. Specifically, ethanol treatment reduces the responsiveness of these neurons to glutamate, delays the expected developmental transitions in patterns of spontaneous activity, and induces increased spontaneous bursting activity, particularly at the stage of dendritic formation. Impairment of responsiveness to glutamate is significant in that it may reflect the compromise by ethanol of a major excitatory pathway in the cerebellar cortex, resulting from the decreased efficacy of glutamatergic input from parallel fibers. In contrast to the results of other studies using adult neurons as a model for the effects of ethanol, our work suggests that the developing CNS neurons does not become tolerant; that is, in the continuing presence of ethanol, it does not express physiological function equivalent to that of the control.     

Membrane estradiol signaling in the brain

While the physiology of membrane-initiated estradiol signaling in the nervous system has remained elusive, a great deal of progress has been made toward understanding the activation of cell signaling. Membrane-initiated estradiol signaling activates G proteins and their downstream cascades, but the identity of membrane receptors and the proximal signaling mechanism(s) have been more difficult to elucidate. Mounting evidence suggests that classical intracellular estrogen receptor-α (ERα) and ERβ are trafficked to the membrane to mediate estradiol cell signaling. Moreover, an interaction of membrane ERα and ERβ with metabotropic glutamate receptors has been identified that explains the pleomorphic actions of membrane-initiated estradiol signaling. This review focuses on the mechanism of actions initiated by membrane estradiol receptors and discusses the role of scaffold proteins and signaling cascades involved in the regulation of nociception, sexual receptivity and the synthesis of neuroprogesterone, an important component in the central nervous system signaling.     

Role of Astroglia and Insulin-Like Growth Factor-I in Gonadal Hormone-Dependent Synaptic Plasticity

Gonadal hormones exert a critical influence over the architecture of specific brain areas affecting the formation of neuronal contacts. Cellular mechanisms mediating gonadal hormone actions on synapses have been studied extensively in the rat arcuate nucleus, a hypothalamic center involved in the feed-back regulation of gonadotropins. Gonadal steroids exert organizational and activational effects on arcuate nucleus synaptic connectivity. Perinatal testosterone induces a sexual dimorphic pattern of synaptic contacts. Furthermore, during the preovulatory and ovulatory phases of the estrous cycle there is a transient disconnection of inhibitory synaptic inputs to the somas of arcuate neurons. This synaptic remodeling is induced by estradiol, blocked by progesterone, and begins with the onset of puberty in females. Astroglia appear to play a significant role in the organizational and the activational hormone effects on neuronal connectivity by regulating the amount of neuronal membrane available for the formation of synaptic contacts and by releasing soluble factors, such as insulin-like growth factor I (IGF-I), which promote the differentiation of neural processes. Recent evidence indicates that gonadal steroids and IGF-I may interact in their trophic effects on the neuroendocrine hypothalamus. Estradiol and IGF-I promote the survival and morphological differentiation of rat hypothalamic neurons in primary cultures. The effect of estradiol depends on IGF-I, while the effects of both estradiol and IGF-I depend on estrogen receptors. Furthermore, estrogen activation of astroglia in hypothalamic tissue fragments depends on IGF-I receptors. These findings indicate that IGF-I may mediate some of the developmental and activational effects of gonadal steroids on the brain and suggest that IGF-I may activate the estrogen receptor to induce its neurotrophic effects on hypothalamic cells. In addition, IGF-I levels in the neuroendocrine hypothalamus are regulated by gonadal steroids. IGF-I levels in tanycytes, a specific astroglia cell type present in the arcuate nucleus and median eminence, increase at puberty, are affected by neonatal androgen levels, show sex differences, and fluctuate in accordance to the natural variations in plasma levels of ovarian steroids that are associated with the estrous cycle. These changes appear to be mediated by hormonal regulation of IGF-I uptake from blood or cerebrospinal fluid by tanycytes. These results suggest that tanycytes may be involved in the regulation of neuroendocrine events in adult rats by regulating the availability of IGF-I to hypothalamic neurons. In summary, IGF-I and different forms of neuron–astroglia communication are involved in the effects of estradiol on synaptic plasticity in the hypothalamic arcuate nucleus.     

Hormonal and humoral influences on brain development

This review discusses evidence for neurotransmitters as developmental signals in such ontogenic processes as neural tube formation (neurulation), germinal cell proliferation, and neuronal and glial differentiation during brain organogenesis, as well as evidence for other roles of these neurotransmitters in non-neuronal tissues of vertebrates and invertebrates. Evidence also is presented for hormonal regulation of brain development during postnatal neurogenesis and for interrelationships which may link neurotransmitters and hormones in a humoral milieu, providing a variety of control mechanisms for the central and peripheral nervous system during key phases of their development. Given the evidence for neurotransmitters and hormones as coordinating influence on neural ontogeny, it is possible that drugs, stress, and environmental influences may have the ability to perturb particular aspects of these developmental systems if present during those "critical periods" when such humoral influences are important for normal ontogeny.     

Sex steroids and brain structure in pubertal boys and girls

Sex steroids exert important organizational effects on brain structure. Early in life, they are involved in brain sexual differentiation. During puberty, sex steroid levels increase considerably. However, to which extent sex steroid production is involved in structural brain development during human puberty remains unknown. The relationship between pubertal rises in testosterone and estradiol levels and brain structure was assessed in 37 boys and 41 girls (10-15 years). Global brain volumes were measured using volumetric-MRI. Regional gray and white matter were quantified with voxel-based morphometry (VBM), a technique which measures relative concentrations ('density') of gray and white matter after individual global differences in size and shape of brains have been removed. Results showed that, corrected for age, global gray matter volume was negatively associated with estradiol levels in girls, and positively with testosterone levels in boys. Regionally, a higher estradiol level in girls was associated with decreases within prefrontal, parietal and middle temporal areas (corrected for age), and with increases in middle frontal-, inferior temporal- and middle occipital gyri. In boys, estradiol and testosterone levels were not related to regional brain structures, nor were testosterone levels in girls. Pubertal sex steroid levels could not explain regional sex differences in regional gray matter density. Boys were significantly younger than girls, which may explain part of the results. In conclusion, in girls, with the progression of puberty, gray matter development is at least in part directly associated with increased levels of estradiol, whereas in boys, who are in a less advanced pubertal stage, such steroid-related development could not (yet) be found. We suggest that in pubertal girls, estradiol may be implicated in neuronal changes in the cerebral cortex during this important period of brain development.     

Puberty: a period of both organizational and activational effects of steroid hormones on neurobehavioural development

During perinatal development, steroid hormones act on the central nervous system (CNS) to organize neural circuits. These circuits remain relatively dormant until hormonal stimulation received in adulthood acts on the CNS to activate adult reproductive physiology and behaviour. In this review, the proposal is put forward that, in addition to perinatal development, puberty serves as another period of neural maturation mediated by both steroid-dependent and -independent events that further organize and shape the behavioural potential of the adult organism. In support of this thesis, data are summarized that clearly show the organizational effects of the pubertal rise in gonadal hormones on mating behaviour and other steroid-mediated behaviours exhibited in adulthood, and on the neural pathways that mediate these behaviours. The importance of determining whether this sensitive period of neural development during puberty is a 'critical period' is also discussed, as well as whether perturbations of the nervous system during pubertal development may result in negative behavioural and physiological outcomes in adulthood. It is concluded that puberty is not merely a time when increasing levels of gonadal steroids activate the neural circuits organized during perinatal development, but also a time of further organization of the CNS, which allows for appropriate behaviours to emerge in adulthood.     

Modulation of 6-hydroxydopamine induced alteration of the postnatal development of central noradrenaline neurons

The effect of substance P and morphine on the 6-hydroxydopamine (6-OHDA) induced alteration of the postnatal development of central noradrenaline (NA) neurons in the rat has been investigated using neurochemical techniques. Neonatal administration of 6-OHDA systemically leads to permanent NA denervations of distant NA projections, while the projections close to the NA cell bodies are increased, leading to NA hyperinnervation. Intracisternal injection of substance P was found to counteract both the NA denervation and hyperinnervation induced by 6-OHDA. The effect of substance P disclosed a clear dose-dependent relationship. Morphine, on the other hand, was observed to potentiate the alterations induced by 6-OHDA, both the NA denervation and hyperinnervation. The effect of morphine was dose-dependent and could be blocked by the morphine antagonist naloxone. The present results give further support for the view that the 6-OHDA induced alteration of the postnatal development of central NA neurons is related to a “pruning effect.” The data furthermore imply that the end-result from a 6-OHDA induced degeneration of central NA neurons during ontogeny may be modulated by the functional state of the neurons.     

Possible Role(s) of Neurokinins in CNS Development and Neurodegenerative or Other Disorders

RAFFA, R.B., Possible role(s) of neurokinins in CNS development and neurodegenerative or other disorders. NEUROSCI BIOBEHAV REV 22(6) 789–813, 1998.—The present review is an attempt to summarize the diverse literature that suggests a role for neurokinins in a variety of CNS developmental or disease processes. The role of neurokinins in (anti)nociception is well known and is the subject of other comprehensive reviews. The focus of this review is on associations that implicate substance P or other neurokinins in certain aspects of CNS development and in various neuropathologic disorders that have neurodegenerative, psychiatric or other clinical manifestations. Also included are associations related to the central control of some “peripheral” functions. The amount and degree of evidence for neurokinin involvement in each situation vary from strong to speculative—critical analyses and commentaries on individual methodologies and studies are available from other sources. When viewed in this broad context, the information suggests intrinsic neuroprotective or neurodegenerative properties of neurokinins. It is proposed that these properties delineate a specialized area within the broader field of neurokinin research.     

Co-culture of oligodendrocytes and neurons can be used to assess drugs for axon regeneration in the central nervous system

We present a novel in vitro model in which to investigate the efficacy of experimental drugs for the promotion of axon regeneration in the central nervous system. We co-cultured rat hippocampal neurons and cerebral cortical oligodendrocytes, and tested the co-culture system using a Nogo-66 receptor antagonist peptide(NEP1–40), which promotes axonal growth. Primary cultured oligodendrocytes suppressed axonal growth in the rat hippocampus, but NEP1–40 stimulated axonal growth in the co-culture system. Our results confirm the validity of the neuron-oligodendrocyte co-culture system as an assay for the evaluation of drugs for axon regeneration in the central nervous system.