Regularities in the formation of structural and functional changes in the brain in technogenic stress

Study of structural and functional changes in the brain under the infl uence of anthropogenic factors showed that limbic brain structures and especially the hippocampus undergo most pronounced reorganization.     

Sex differences in synaptic plasticity in stress-responsive brain regions following chronic variable stress

Increased stress responsiveness is implicated in the etiology of mood and anxiety disorders, including depression and post-traumatic stress disorder. Additionally, stress-related affective disorders have a higher incidence in women than men. Chronic stress in rodents produces numerous neuromorphological changes in a variety of limbic brain regions. Here, we examined the sex-dependent differences in presynaptic innervation of the paraventricular nucleus of the hypothalamus (PVN), prefrontal cortex (PFC), bed nucleus of the stria terminalis (BST), and amygdala in response to chronic variable stress (CVS). Following 14 days of CVS, the presynaptic protein synaptophysin was assessed in male and female rats. Our results demonstrate that synaptophysin staining density was higher in females than males in all brain areas evaluated, indicating sex differences in the organization of presynaptic innervation. After CVS, the PVN, principal nucleus of the BST (BSTpr), and basolateral nucleus of the amygdala (BLA) displayed significantly reduced synaptophysin density in females but not males. Furthermore, males showed an increase in synaptophysin in the PVN after CVS, suggesting a sex difference in the modulation of presynaptic inputs to the PVN following chronic stress. Overall, these data suggest marked sex differences in PVN, BSTpr, and BLA presynaptic innervation as a consequence of chronic stress, which may be associated with differential stress responsivity and perhaps susceptibility to pathologies in males and females.     

PSA-NCAM in mammalian structural plasticity and neurogenesis

Polysialic acid (PSA) is a linear homopolymer of alpha2-8-N acetylneuraminic acid whose major carrier in vertebrates is the neural cell adhesion molecule (NCAM). PSA serves as a potent negative regulator of cell interactions via its unusual biophysical properties. PSA on NCAM is developmentally regulated thus playing a prominent role in different forms of neural plasticity spanning from embryonic to adult nervous system, including axonal growth, outgrowth and fasciculation, cell migration, synaptic plasticity, activity-induced plasticity, neuronal-glial plasticity, embryonic and adult neurogenesis. The cellular distribution, developmental changes and possible function(s) of PSA-NCAM in the central nervous system of mammals here are reviewed, along with recent findings and theories about the relationships between NCAM protein and PSA as well as the role of different polysialyltransferases. Particular attention is focused on postnatal/adult neurogenesis, an issue which has been deeply investigated in the last decade as an example of persisting structural plasticity with potential implications for brain repair strategies. Adult neurogenic sites, although harbouring all subsequent steps of cell differentiation, from stem cell division to cell replacement, do not faithfully recapitulate development. After birth, they undergo morphological and molecular modifications allowing structural plasticity to adapt to the non-permissive environment of the mature nervous tissue, that are paralled by changes in the expression of PSA-NCAM. The use of PSA-NCAM as a marker for exploring differences in structural plasticity and neurogenesis among mammalian species is also discussed.     

Endocannabinoid signaling and synaptic plasticity in the brain

Repetitive firing neuron or activation of synaptic transmission plays an important role in the modulation of synaptic efficacy, such as long-term potentiation (LTP) and long-term depression (LTD). These activity-dependent changes in synaptic efficacy are thought to be critical to learning and memory; however, the underlying mechanisms remain to be defined. Endogenous cannabinoids (eCBs) are diffusible modulators that are released from depolarized postsynaptic neurons and act on presynaptic terminals. Persistent release of eCBs can lead to long-term modulation of synaptic plasticity in the brain. Given a broad distribution of eCB receptors in the brain, the eCB signaling system could contribute to use-dependent modification of brain functions.     

Sleep-dependent motor memory plasticity in the human brain

Growing evidence indicates a role for sleep in off-line memory processing, specifically in post-training consolidation. In humans, sleep has been shown to trigger overnight learning on a motor-sequence memory task, while equivalent waking periods produce no such improvement. But while the behavioral characteristics of sleep-dependent motor learning become increasingly well characterized, the underlying neural basis remains unknown. Here we present functional magnetic resonance imaging data demonstrating a change in the representation of a motor memory after a night of sleep. Subjects trained on a motor-skill memory and 12 hours later, after either sleep or wake, were retested during functional magnetic resonance imaging. Following sleep relative to wake, regions of increased activation were expressed in the right primary motor cortex, medial prefrontal lobe, hippocampus and left cerebellum; changes that can support faster motor output and more precise mapping of key-press movements. In contrast, signal decreases were identified in parietal cortices, the left insular cortex, temporal pole and fronto-polar region, reflecting a reduced need for conscious spatial monitoring and a decreased emotional task burden. This evidence of an overnight, systems-level change in the representation of a motor memory holds important implications for acquiring real-life skills and in clinical rehabilitation following brain trauma, such as stroke.     

Synaptic plasticity in the sex steroid-sensitive neuroendocrine brain

Sex steroids are known to modulate neural development and neural circuit formation in both developing and adult sex steroid-sensitive neuroendocrine brain of mammals. During perinatal period, estrogen or aromatizable androgen can act as a neurotropic factor on neural tissues, stimulating axonal and dendritic growth and synapse formation. The development of sexual dimorphic synaptic organization may reflect sex steroid-modulating synaptogenesis in the hypothalamus and limbic system during perinatal period. The onset of puberty may also be due, at least in part, to stimulation of synapse formation by estrogen in the hypothalamus. In adulthood, estrogen has a facilitatory effect on synapse formation in neural structures such as septum, hypothalamus and midbrain with or without brain lesion, and androgen plays a significant role in regulating synaptic remodeling in the androgen-sensitive spinal motoneuron pools. Thus, sex steroids seems to be critical from developmental period to adulthood for organizing and reorganizing neuronal circuitry driving neuroendocrine and behavioral functions.     

Synaptic structural organization as a determinant of selective sensitivity and plasticity of brain neurons in postanoxic period]

The neuro- and synaptoarchitectonics of the sensoty-motor cortex of the brain and cerebellum was comparatively analyzed in an experiment on adult albino rats. There was a relationship between the formation of axospinal synapses to the type of organization of paramembranous cytoskeleton. A role of cytoskeleton's factors of synaptic contacts in the pathogenesis of postanoxic selective neuronal lesion and in the compensatory reorganization of synaptoarchitectonics is hypothesized.     

New scenarios for neuronal structural plasticity in non-neurogenic brain parenchyma: the case of cortical layer II immature neurons

The mammalian central nervous system, due to its interaction with the environment, must be endowed with plasticity. Conversely, the nervous tissue must be substantially static to ensure connectional invariability. Structural plasticity can be viewed as a compromise between these requirements. In adult mammals, brain structural plasticity is strongly reduced with respect to other animal groups in the phylogenetic tree. It persists under different forms, which mainly consist of remodeling of neuronal shape and connectivity, and, to a lesser extent, the production of new neurons. Adult neurogenesis is mainly restricted within two neurogenic niches, yet some gliogenic and neurogenic processes also occur in the so-called non-neurogenic tissue, starting from parenchymal progenitors. In this review we focus on a population of immature, non-newly generated neurons in layer II of the cerebral cortex, which were previously thought to be newly generated since they heavily express the polysialylated form of the neural cell adhesion molecule and doublecortin. These unusual neurons exhibit characteristics defining an additional type of structural plasticity, different from either synaptic plasticity or adult neurogenesis. Evidences concerning their morphology, antigenic features, ultrastructure, phenotype, origin, fate, and reaction to different kind of stimulations are gathered and analyzed. Their possible role is discussed in the context of an enriched complexity and heterogeneity of mammalian brain structural plasticity.     

Repeated immobilization stress in the early postnatal period increases stress response in adult rats

Repeated immobilization stress tests in the early postnatal period were performed to determine the effects on the growth of developing rats as well as the response of the HPA axis to subsequent novel stress in adulthood. In addition, effects of maternal deprivation (MD) with the same period of the exposure to immobilization stress were also examined. We used 2 different types of immobilization stress and 2 different types of MD: immobilization stress for 30 min/day from postnatal day 7 (P7) to P13 (IS7-13 group); immobilization stress for 30 min on P7 (IS7 group); MD for 30 min/day from P7 to P13 (MD7-13 group); and MD for 30 min on P7 (MD7 group). Body weights were lower in the IS7-13 group than in the control group from P10 to P50, although body weight gain in the MD7-13 group was only transiently affected. Stress-induced corticosterone levels in the IS7-13 group were higher than in the control group and did not return to baseline levels until at least 120 min after the termination of stress, whereas temporal variations of stress-induced corticosterone levels did not differ between the IS, MD7-13, MD7, and control groups. Repeated immobilization stress in the early postnatal period induced long-term effects on the growth of developing rats and stress response of the HPA axis to the novel stress in adulthood, although a single immobilization stress, periodic MD, or a single MD had little effect.     

Activity-dependent structural and functional plasticity of astrocyte-neuron interactions

Observations from different brain areas have established that the adult nervous system can undergo significant experience-related structural changes throughout life. Less familiar is the notion that morphological plasticity affects not only neurons but glial cells as well. Yet there is abundant evidence showing that astrocytes, the most numerous cells in the mammalian brain, are highly mobile. Under physiological conditions as different as reproduction, sensory stimulation, and learning, they display a remarkable structural plasticity, particularly conspicuous at the level of their lamellate distal processes that normally ensheath all portions of neurons. Distal astrocytic processes can undergo morphological changes in a matter of minutes, a remodeling that modifies the geometry and diffusion properties of the extracellular space and relationships with adjacent neuronal elements, especially synapses. Astrocytes respond to neuronal activity via ion channels, neurotransmitter receptors, and transporters on their processes; they transmit information via release of neuroactive substances. Where astrocytic processes are mobile then, astrocytic-neuronal interactions become highly dynamic, a plasticity that has important functional consequences since it modifies extracellular ionic homeostasis, neurotransmission, gliotransmission, and ultimately neuronal function at the cellular and system levels. Although a complete picture of intervening cellular mechanisms is lacking, some have been identified, notably certain permissive molecular factors common to systems capable of remodeling (cell surface and extracellular matrix adhesion molecules, cytoskeletal proteins) and molecules that appear specific to each system (neuropeptides, neurotransmitters, steroids, growth factors) that trigger or reverse the morphological changes.     

Morphological plasticity of dendrites in adult brain

Deafferentation of certain brain regions in adult animals results in (1) the disappearance of degenerating axon terminals and (2) in the temporary persistence of vacant postsynaptic sites. These postsynaptic sites were shown to be re-supplied by sprouted axon terminals of intact axons. It is described in this paper, that in brain regions (e.g. cerebellar cortex, lateral geniculate nucleus) where axonal sprouting of local elements or of persisting afferent axons is negligible or absent, synaptic reorganization occurs via the active participation of postsynaptic dendritic and somatic elements of surviving local nerve cells. The dendrites may develop two types of reaction upon deafferentation (1) formation of presynaptic specializations along their otherwise "classical" postsynaptic membrane, resulting in the formation of new, dendro-dendritic synapses and (2) the "adaptive" (structural) reduction in size of denervated nerve cell dendritic arbor, leading to a relative increase in density of the surviving (though non-sprouting) afferent axon terminals. A partial functional recovery in both cases is also demonstrated.     

Chronic restraint stress and chronic corticosterone treatment modulate differentially the expression of molecules related to structural plasticity in the adult rat piriform cortex

Stress and stress-related hormones induce structural changes in neurons of the adult CNS. Neurons in the hippocampus, the amygdala and the prefrontal cortex undergo neurite remodeling after chronic stress. In the hippocampus some of these effects can be mimicked with chronic administration of adrenal steroids. These changes in neuronal structure may be mediated by certain molecules related to plastic events such as the polysialylated form of the neural cell adhesion molecule (PSA-NCAM). The expression of PSA-NCAM persists in the adult hippocampus and it is up-regulated after chronic stress. The piriform cortex also displays considerable levels of PSA-NCAM during adulthood and indirect evidence suggests that it may also be the target of stress and stress related-hormones. Using immunohistochemistry we have studied the expression of PSA-NCAM and doublecortin (DCX; another protein implicated in neuronal structural plasticity) in the piriform cortex of adult rats subjected either to 21 days of chronic restraint stress or to oral corticosterone administration during the same period. Our results indicate that chronic stress and chronic corticosterone administration have differential effects on the expression of PSA-NCAM and DCX. While chronic stress increases the number of PSA-NCAM- and DCX-immunoreactive cells in the piriform cortex layer II, chronic corticosterone administration decreases these numbers. These findings indicate that stress and adrenal steroids affect the piriform cortex and suggest that in this region, as in the hippocampus, they may induce structural changes. This is a potential mechanism by which stress and corticosterone modulate functions of this limbic region, such as its participation in olfactory memory.     

Obesity/hyperleptinemic phenotype impairs structural and functional plasticity in the rat hippocampus

Epidemiological studies estimate that greater than 60% of the adult US population may be categorized as either overweight or obese, and there is a growing appreciation that the complications of obesity extend to the central nervous system (CNS). While the vast majority of these studies have focused on the hypothalamus, more recent studies suggest that the complications of obesity may also affect the structural and functional integrity of the hippocampus. A potential contributor to obesity-related CNS abnormalities is the adipocyte-derived hormone leptin. In this regard, decreases in CNS leptin activity may contribute to deficits in hippocampal synaptic plasticity and suggest that leptin resistance, a well-described phenomenon in the hypothalamus, may also be observed in the hippocampus. Unfortunately, the myriad of metabolic and endocrine abnormalities in diabetes/obesity phenotypes makes it challenging to assess the role of leptin in hippocampal neuroplasticity deficits associated with obesity models. To address this question, we examined hippocampal morphological and behavioral plasticity following lentivirus-mediated downregulation of hypothalamic insulin receptors (hypo-IRAS). Hypo-IRAS rats exhibit increases in body weight, adiposity, plasma leptin and triglyceride levels. As such, hypo-IRAS rats develop a phenotype that is consistent with features of the metabolic syndrome. In addition, hippocampal morphological plasticity and performance of hippocampal-dependent tasks are adversely affected in hypo-IRAS rats. Leptin-mediated signaling is also decreased in hypo-IRAS rats. We will discuss these findings in the context of how hyperleptinemia and hypertriglyceridemia may represent mechanistic mediators of the neurological consequences of impaired hippocampal synaptic plasticity in obesity.     

Repeated social defeat stress induces chronic hyperthermia in rats

Psychological stressors are known to increase core body temperature (T_c) in laboratory animals. Such single stress-induced hyperthermic responses are typically monophasic, as T_c returns to baseline within several hours. However, studies on the effects of repeated psychological stress on T_c are limited. Therefore, we measured T_c changes in male Wistar rats after they were subjected to 4 social defeat periods (each period consisting of 7 daily 1 h stress exposures during the light cycle followed by a stress-free day). We also assessed affective-like behavioral changes by elevated plus maze and forced swim tests.In the stressed rats, the first social defeat experience induced a robust increase in T_c (+ 1.3 °C). However, the T_c of these rats was not different from control animals during the subsequent dark period. In comparison, after 4 periods of social defeat, stressed rats showed a small but significantly higher (+ 0.2-0.3 °C) T_c versus control rats during both light and dark periods. Stressed rats did not show increased anxiety-like behavior versus control rats as assessed by the elevated plus maze test. However, in the forced swim test, the immobility time of stressed rats was significantly longer versus control rats, suggesting an increase in depression-like behavior. Furthermore, hyperthermia and depression-like behavior were still observed 8 days after cessation of the final social defeat session. These results suggest that repeated social defeat stress induces a chronic hyperthermia in rats that is associated with behavior resembling depression but not anxiety.     

Behavioral manifestations of brain plasticity in blind and low-vision individuals

Tactile sensitivity enhancement (TSE) observed in blind people is probably a result of intensified tactile training. Although many researchers consider TSE in the blind to be an example of use-dependent plasticity, it is unclear whether the effects of training (Braille reading) are specific, i.e. restricted to the trained function and hand, or if they are more general. To examine this issue further, blind Braille readers, low-vision subjects (Braille readers and non-Braille readers) and sighted controls were tested in two tasks: a texture task resembling the Braille system and a dissimilar groove orientation task. Braille readers, both blind and those with low vision, performed better in both tasks than low-vision non-Braille readers or sighted controls. However, the difference was significant only for the blind (more experienced) Braille readers. In the groove orientation task, the positive influence of training was detectable irrespective of the hand used in the test, but in the coarse texture task this influence was limited to the hand trained in Braille. Thus, it appears that tactile training is of significance in TSE but its effects are, to a large extent, task- and hand-specific.     

Neurons,glia, and plasticity in normal brain aging

Early manifestations of brain aging have received much less attention than the drastic degeneration of AD and MID. During nonpathological changes of normal aging, brain systems differ in the involvement of neuron loss. Spatial learning can become impaired without evidence for neuron loss, whereas eye-blink conditioning deficits are well correlated with Purkinje neuron loss. Glial activation, in particular the increased expression of glial fibrillary acidic protein (GFAP), may be a factor in impaired synaptic plasticity. Lastly, it is discussed how developmental variations in the numbers of Purkinje cells and ovarian oocytes can be factors in outcomes of aging that are not under strict genetic control.     

Multimodality multidimensional image analysis of cortical and subcortical plasticity in the rat brain

In this work, we developed and implemented a multimodality multidimensional imaging system which is capable of generating and displaying anatomical and functional images of selected structures and processes within a vertebrate's central nervous system (CNS). The functional images are generated from [¹⁴C]-2-deoxy-d-glucose (2DG) autoradiography whereas the anatomic images are derived from cytochrome oxidase (CO) histochemistry. This multi-modality imaging system has been used to study mechanisms underlying information processing in the rat brain. We have applied this technique to visualize and measure the plasticity (deformation) observed in the rat's whisker system due to neonatal lesioning of selected peripheral sensory organs. Application of this imaging system revealed detailed information about the shape, size, and directionality of selected cortical and subcortical structures. Previous 2-D imaging techniques were unable to deliver such holistic information. Another important issue addressed in this work is related to image registration problems. We developed an image registration technique which employs extrinsic fiduciary marks for alignment and is capable of registering images with subpixel accuracy. It uses the information from all available fiduciary marks to promote alignment of the sections and to avoid propagation of errors across a serial data set.