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The progressive aging of the population will notably increase the burden of those diseases which leads to a disabling situation, such as Alzheimer's disease (AD) and ophthalmological diseases that cause a visual impairment (VI). Eye diseases that cause a VI raise neuroplastic processes in the parietal lobe. Meanwhile, the aforementioned lobe suffers a severe decline throughout AD. From this perspective, diving deeper into the particularities of the parietal lobe is of paramount importance. In this article, we discuss the functions of the parietal lobe, review the parietal anatomical and pathophysiological peculiarities in AD, and also describe some of the changes in the parietal region that occur after VI. Although the alterations in the hippocampus and the temporal lobe have been well documented in AD, the alterations of the parietal lobe have been less thoroughly explored. Recent neuroimaging studies have revealed that some metabolic and perfusion impairments along with a reduction of the white and grey matter could take place in the parietal lobe during AD. Conversely, it has been speculated that blinding ocular diseases induce a remodeling of the parietal region which is observable through the improvement of the integration of multimodal stimuli and in the increase of the volume of this cortical region. Based on current findings concerning the parietal lobe in both pathologies, we hypothesize that the increased activity of the parietal lobe in people with VI may diminish the neurodegeneration of this brain region in those who are visually impaired by oculardiseases. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) is a powerful neurostimulation therapy proposed for the treatment of several neuropsychiatric disorders. However, DBS mechanism of action remains unclear, being its effects on brain dynamics of particular interest. Specifically, DBS reversibility is a major point of debate. Preclinical studies in obesity showed that the stimulation of the lateral hypothalamus (LH) and nucleus accumbens (NAcc), brain centers involved in satiety and reward circuits, are able to modulate the activity of brain structures impaired in this pathology. Nevertheless, the long-term persistence of this modulation after DBS withdrawal was unexplored. Here we examine the in vivo presence of such changes 1 month after LH- and NAcc-DBS, along with differences in synaptic plasticity, following an exploratory approach. Thus, both stimulated and non-stimulated animals with electrodes in the NAcc showed a common pattern of brain metabolism modulation, presumably derived from the electrodes' presence. In contrast, animals stimulated in the LH showed a relative metabolic invariance, and a reduction of neuroplasticity molecules, evidencing long-lasting neural changes. Our findings suggest that the reversibility or persistence of DBS modulation in the long-term depends on the selected DBS target. Therefore, the DBS footprint would be influenced by the stability achieved in the neural network involved during the stimulation. [ABSTRACT FROM AUTHOR]

Erythropoietin (EPO), named after its role in hematopoiesis, is also expressed in mammalian brain. In clinical settings, recombinant EPO treatment has revealed a remarkable improvement of cognition, but underlying mechanisms have remained obscure. Here, we show with a novel line of reporter mice that cognitive challenge induces local/endogenous hypoxia in hippocampal pyramidal neurons, hence enhancing expression of EPO and EPO receptor (EPOR). High-dose EPO administration, amplifying auto/paracrine EPO/EPOR signaling, prompts the emergence of new CA1 neurons and enhanced dendritic spine densities. Single-cell sequencing reveals rapid increase in newly differentiating neurons. Importantly, improved performance on complex running wheels after EPO is imitated by exposure to mild exogenous/inspiratory hypoxia. All these effects depend on neuronal expression of the Epor gene. This suggests a model of neuroplasticity in form of a fundamental regulatory circle, in which neuronal networks—challenged by cognitive tasks—drift into transient hypoxia, thereby triggering neuronal EPO/EPOR expression. EPO treatment improves cognition, but underlying mechanisms were unknown. Here the authors describe a regulatory loop in which brain networks challenged by cognitive tasks drift into functional hypoxia that drives—via neuronal EPO synthesis—neurodifferentiation and dendritic spine formation. [ABSTRACT FROM AUTHOR]

N-methyl-D-aspartate receptors (NMDARs) are present in both pyramidal neurons and interneurons of the hippocampus. These receptors play an important role in the adult structural plasticity of excitatory neurons, but their impact on the remodeling of interneurons is unknown. Among hippocampal interneurons, somatostatin-expressing cells located in the stratum oriens are of special interest because of their functional importance and structural characteristics: they display dendritic spines, which change density in response to different stimuli. In order to understand the role of NMDARs on the structural plasticity of these interneurons, we have injected acutely MK-801, an NMDAR antagonist, to adult mice which constitutively express enhanced green fluorescent protein (EGFP) in these cells. We have behaviorally tested the animals, confirming effects of the drug on locomotion and anxiety-related behaviors. NMDARs were expressed in the somata and dendritic spines of somatostatin-expressing interneurons. Twenty-four hours after the injection, the density of spines did not vary, but we found a significant increase in the density of their en passant boutons (EPB). We have also used entorhinohippocampal organotypic cultures to study these interneurons in real-time. There was a rapid decrease in the apparition rate of spines after MK-801 administration, which persisted for 24 h and returned to basal levels afterwards. A similar reversible decrease was detected in spine density. Our results show that both spines and axons of interneurons can undergo remodeling and highlight NMDARs as regulators of this plasticity. These results are specially relevant given the importance of all these players on hippocampal physiology and the etiopathology of certain psychiatric disorders. [ABSTRACT FROM AUTHOR]

Neuronal plasticity peaks during critical periods of postnatal development and is reduced towards adulthood. Recent data suggests that windows of juvenile-like plasticity can be triggered in the adult brain by antidepressant drugs such as Fluoxetine. Although the exact mechanisms of how Fluoxetine promotes such plasticity remains unknown, several studies indicate that inhibitory circuits play an important role. The polysialylated form of the neural cell adhesion molecules (PSA-NCAM) has been suggested to mediate the effects of Fluoxetine and it is expressed in the adult brain by mature interneurons. Moreover, the enzymatic removal of PSA by neuroaminidase-N not only affects the structure of interneurons but also has been shown to play a role in the onset of critical periods during development. We have here used ocular dominance plasticity in the mouse visual cortex as a model to investigate whether removal of PSA might influence the Fluoxetine-induced plasticity. We demonstrate that PSA removal in the adult visual cortex alters neither the baseline ocular dominance, nor the fluoxetine-induced shift in the ocular dominance. We also show that both chronic Fluoxetine treatment and PSA removal independently increase the basal FosB expression in parvalbumin (PV) interneurons in the primary visual cortex. Therefore, our data suggest that although PSA-NCAM regulates inhibitory circuitry, it is not required for the reactivation of juvenilelike plasticity triggered by Fluoxetine. [ABSTRACT FROM AUTHOR]

Novel hypotheses suggest that antidepressants, such as the selective serotonin reuptake inhibitor fluoxetine, induce neuronal structural plasticity, resembling that of the juvenile brain, although the underlying mechanisms of this reopening of the critical periods still remain unclear. However, recent studies suggest that inhibitory networks play an important role in this structural plast2city induced by fluoxetine. For this reason we have analysed the effects of a chronic fluoxetine treatment in the hippocampus and medial prefrontal cortex (mPFC) of transgenic mice displaying eGFP labelled interneurons. We have found an increase in the expression of molecules related to critical period plasticity, such as the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), GAD67/65 and synaptophysin, as well as a reduction in the number of parvalbumin expressing interneurons surrounded by perineuronal nets. We have also described a trend towards decrease in the perisomatic inhibitory puncta on pyramidal neurons in the mPFC and an increase in the density of inhibitory puncta on eGFP interneurons. Finally, we have found that chronic fluoxetine treatment affects the structure of interneurons in the mPFC, increasing their dendritic spine density. The present study provides evidence indicating that fluoxetine promotes structural changes in the inhibitory neurons of the adult cerebral cortex, probably through alterations in plasticity-related molecules of neurons or the extracellular matrix surrounding them, which are present in interneurons and are known to be crucial for the development of the critical periods of plasticity in the juvenile brain. [ABSTRACT FROM AUTHOR]

Neuronal structural plasticity is known to have a major role in cognitive processes and in the response of the CNS to aversive experiences. This type of plasticity involves processes ranging from neurite outgrowth/retraction or dendritic spine remodeling, to the incorporation of new neurons to the established circuitry. However, the study of how these structural changes take place has been focused mainly on excitatory neurons, while little attention has been paid to interneurons. The exploration of these plastic phenomena in interneurons is very important, not only for our knowledge of CNS physiology, but also for understanding better the etiology of different psychiatric and neurological disorders in which alterations in the structure and connectivity of inhibitory networks have been described. Here we review recent work on the structural remodeling of interneurons in the adult brain, both in basal conditions and after chronic stress or sensory deprivation. We also describe studies from our laboratory and others on the putative mediators of this interneuronal structural plasticity, focusing on the polysialylated form of the neural cell adhesion molecule (PSA-NCAM). This molecule is expressed by some interneurons in the adult CNS and, through its anti-adhesive and insulating properties, may participate in the remodeling of their structure. Finally, we review recent findings on the possible implication of PSA-NCAM on the remodeling of inhibitory neurons in certain psychiatric disorders and their treatments. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Administration of NMDA receptor antagonists upregulates the expression of the polysialylated form of the neural cell adhesion molecule (PSA-NCAM) in the adult hippocampus. Since the piriform cortex is also populated by PSA-NCAM immunoreactive neurons during adulthood, we sought to characterize them in detail and to test whether NMDA receptor antagonists also modulate PSA-NCAM in this cortical region. PSA-NCAM immunoreactivity is located mainly in layer II, where many neurogliaform and some pyramidal–semilunar transitional neurons are labeled. Many large neurons in layer III and endopiriform nucleus also express PSA-NCAM. Interestingly, some small labeled cells resembling migratory neuroblasts appear in these layers and in the ventral end of the corpus callosum subjacent to the piriform cortex. These putative migratory cells and some neurogliaform neurons in layer II do not express NeuN, a marker of differentiated neurons. Many of these PSA-NCAM immunoreactive cells also express doublecortin, a molecule involved in neuronal migration. The number of PSA-NCAM immunoreactive neurogliaform neurons increases significantly 7 days after the administration of an NMDA receptor antagonist. Moreover, 21 days after the treatment we observe a significant increase in the number of doublecortin expressing cells in the deep layers of the piriform cortex. These results expand the current knowledge of the neuronal populations expressing PSA-NCAM in the piriform cortex, suggesting that some of these cells could be involved in structural plastic events such as axonal outgrowth, synaptogenesis or even neuronal migration. Similar to the hippocampus, NMDA receptors appear to play a critical role in these processes in the adult piriform cortex. [Copyright &y& Elsevier]

Down syndrome (DS) is the most common genetic disorder associated with intellectual disability. To study this syndrome, several mouse models have been developed. Among the most common is the Ts65Dn model, which mimics most of the alterations observed in DS. Ts65Dn mice, as humans with DS, show defects in the structure, density, and distribution of dendritic spines in the cerebral cortex and hippocampus. Fasudil is a potent inhibitor of the RhoA kinase pathway, which is involved in the formation and stabilization of dendritic spines. Our study analysed the effect of early chronic fasudil treatment on the alterations observed in the hippocampus of the Ts65Dn model. We observed that treating Ts65Dn mice with fasudil induced an increase in neural plasticity in the hippocampus: there was an increment in the expression of PSA-NCAM and BDNF, in the dendritic branching and spine density of granule neurons, as well as in cell proliferation and neurogenesis in the subgranular zone. Finally, the treatment reduced the unbalance between excitation and inhibition present in this model. Overall, early chronic treatment with fasudil increases cell plasticity and eliminates differences with euploid animals. • Fasudil treatment recovers dendritic trees in granule neurons of Ts65Dn mice. • Fasudil treatment increases spine density in granule neurons of Ts65Dn mice. • Fasudil treatment increases structural plasticity in the hippocampus of Ts65Dn mice. • Fasudil treatment recovers cell proliferation rate in dentate gyrus of Ts65Dn mice. • Fasudil infusion reduces the excess of inhibitory puncta in the hippocampus of Ts65Dn. [ABSTRACT FROM AUTHOR]

Abstract: Several lines of evidence indicate that alterations in the structure of neural circuits and inhibitory neurotransmission underlie the physiopathogenesis of schizophrenia. Most of the studies on these parameters have been focused on cortical regions and, despite the crucial role of the amygdala in this psychiatric disorder, there is less information on this region. In order to expand this knowledge, we have studied the expression of molecules related to inhibitory neurotransmission and structural plasticity in rats subjected to post-weaning isolation rearing, an animal model that reproduces several core symptoms of schizophrenia. We have analyzed, using qRT-PCR and immunohistochemistry, the expression of synaptophysin, GAD65, GAD67, the neural cell adhesion molecule (NCAM), its polysialylated form (PSA-NCAM) and its synthesizing enzymes (St8siaII and St8SiaIV). Isolation-reared rats showed significant increases in the expression of GAD67 protein in the centromedial, medial and basolateral amygdaloid nuclei, but no significant changes in GAD65 or synaptophysin expression were found in these regions. The expression of PSA-NCAM and NCAM was significantly increased in the basolateral and medial nuclei respectively. Our results indicate that isolation-rearing influences positively inhibitory neurotransmission and neuronal structural plasticity in the amygdala, probably through PSA-NCAM. These findings are in contrast to reports describing decreased expression of molecules related to inhibitory neurotransmission in the amygdala of schizophrenic patients. Consequently, although the social isolation rearing model can reproduce some of the behavioral traits of schizophrenics it may fail to reproduce some of the neurobiological features of this disorder, particularly in the amygdala. [Copyright &y& Elsevier]

Diabetes mellitus patients are at increased risk of developing depression, although the neurobiological bases of this comorbidity are not yet fully understood. These patients show CNS alterations, similar to those found in major depression, including changes in the structure and neurotransmission of excitatory neurons. However, although depressive patients and animal models also display alterations in inhibitory networks, little is known about the effects of diabetes on interneurons. Our main objective was to study the impact of diabetes on interneurons of the medial prefrontal cortex (mPFC), one of the regions most affected by major depression. For this purpose we have induced diabetes with high-dose streptozotozin in transgenic mice displaying fluorescent interneurons. These animals showed a depressive-like behavior (increased immobility time in tail suspension test) in parallel with reductions in interneuronal dendritic arborization and in the expression of GAD67, the enzyme that synthetizes the inhibitory neurotransmitter GABA. However, the levels of PSA-NCAM, a plasticity-related molecule exclusively expressed by interneurons in the mPFC, were unaltered in the different regions and layers of this cortical area. Interestingly, diabetic mice also showed increased levels of synaptophysin, a synaptic vesicle protein. These results indicate that the structure and neurotransmission of interneurons is altered in the mPFC of diabetic mice and suggest that these changes may play a key role in the depressive symptoms associated to diabetes. [ABSTRACT FROM AUTHOR]

Abstract: Neuroimaging has revealed structural abnormalities in the amygdala of different psychiatric disorders. The polysialylated neural cell adhesion molecule (PSA-NCAM), a molecule related to neuronal structural plasticity, which expression is altered in schizophrenia, major depression and in animal models of these disorders, may participate in these changes. However, PSA-NCAM has not been studied in the human amygdala. To know whether its expression and that of presynaptic markers, was affected in psychiatric disorders, we have analyzed post-mortem sections from the Stanley Neuropathology Consortium, which includes controls, schizophrenia, bipolar and major depression patients. PSA-NCAM was expressed in neuronal somata and neuropil puncta, many of which corresponded to interneurons. Depressed patients showed decreases in PSA-NCAM expression in the basolateral and basomedial amygdala; synaptophysin and GAD67 were also decreased, while VGLUT-1 was increased, in different nuclei. Increases in PSA-NCAM expression were found in the lateral nucleus of bipolar patients; synaptophysin and GAD67 were reduced, and VGLUT-1 increased, in their basolateral and lateral nuclei. The expression of synaptophysin and GAD67 was downregulated in the basolateral nucleus of schizophrenics. These results indicate that inhibitory and excitatory amygdaloid circuits are affected in these disorders and that abnormal PSA-NCAM expression in depressive and bipolar patients may underlie these alterations. [Copyright &y& Elsevier]

Abstract: Chronic stress in experimental animals, one of the most accepted models of chronic anxiety and depression, induces structural remodeling of principal neurons in the amygdala and increases its excitation by reducing inhibitory tone. These changes may be mediated by the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), a molecule related to neuronal structural plasticity and expressed by interneurons in the adult CNS, which is downregulated in the amygdala after chronic stress. We have analyzed the amygdala of adult mice after 21days of restraint stress, studying with qRT-PCR the expression of genes related to general and inhibitory neurotransmission, and of PSA synthesizing enzymes. The expression of GAD67, synaptophysin and PSA-NCAM was also studied in specific amygdaloid nuclei using immunohistochemistry. We also analyzed dendritic arborization and spine density, and cell activity, monitoring c-Fos expression, in amygdaloid interneurons. At the mRNA level, the expression of GAD67 and of St8SiaII was significantly reduced. At the protein level there was an overall reduction in the expression of GAD67, synaptophysin and PSA-NCAM, but significant changes were only detected in specific amygdaloid regions. Chronic stress did not affect dendritic spine density, but reduced dendritic arborization in interneurons of the lateral and basolateral amygdala. These results indicate that chronic stress modulates inhibitory neurotransmission in the amygdala by regulating the expression of molecules involved in this process and by promoting the structural remodeling of interneurons. The addition of PSA to NCAM by St8SiaII may be involved in these changes. [Copyright &y& Elsevier]