On the role of the extracellular space on the holistic behavior of the brain

Marcoli, Manuela; Agnati, Luigi F.; Benedetti, Francesco; Genedani, Susanna; Guidolin, Diego; Ferraro, Luca; Maura, Guido; Fuxé, Kjell

doi:10.1515/revneuro-2015-0007

Cited by 37 publications

(33 citation statements)

References 130 publications

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“…The ECM creates an interface between cells to provide structural support and mechanical strength to tissue, but also exerts juxtacrine signaling, resulting in functional effects on constituent cells [1]. The decellularization of tissues affords the reformulation of ECM as a bioscaffold that conveys structural, as well as functional properties in aiding and enhancing soft tissue repair [2].…”

Section: Introductionmentioning

confidence: 99%

Long-term retention of ECM hydrogel after implantation into a sub-acute stroke cavity reduces lesion volume

et al. 2017

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Salvaging or functional replacement of damaged tissue caused by stroke in the brain remains a major therapeutic challenge. In situ gelation and retention of a hydrogel bioscaffold composed of 8 mg/mL extracellular matrix (ECM) can induce a robust invasion of cells within 24 hours and potentially promote a structural remodeling to replace lost tissue. Herein, we demonstrate a long-term retention of ECM hydrogel within the lesion cavity. A decrease of approximately 32% of ECM volume is observed over 12 weeks. Lesion volume, as measured by magnetic resonance imaging and histology, was reduced by 28%, but a battery of behavioral tests (bilateral asymmetry test; footfault; rotameter) did not reveal a therapeutic or detrimental effect of the hydrogel. Glial scarring and peri-infarct astrocytosis were equivalent between untreated and treated animals, potentially indicating that permeation into host tissue is required to exert therapeutic effects. These results reveal a marked difference of biodegradation of ECM hydrogel in the stroke-damaged brain compared to peripheral soft tissue repair. Further exploration of these structure-function relationships is required to achieve a structural remodeling of the implanted hydrogel, as seen in peripheral tissues, to replace lost tissue and promote behavioral recovery.

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Section: Introductionmentioning

confidence: 99%

Long-term retention of ECM hydrogel after implantation into a sub-acute stroke cavity reduces lesion volume

et al. 2017

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“…Magnetic fields greater than the 3 T employed for 1 H-MRS in this study are necessary to separate signals for glutamine and glutamate reliably. Additionally, there is growing recognition of the role of neuroactive chemicals in the extracellular matrix on intercellular communication in the brain (Marcoli et al, 2015). Nevertheless, it is notable that glutamatergic metabolites in the primary motor cortex demonstrated associations with the RMT, and further research is necessary to characterize the mechanisms by which glutamate mediates this aspect of excitatory physiology.…”

Section: Discussionmentioning

confidence: 99%

An Exploratory Study of Spectroscopic Glutamatergic Correlates of Cortical Excitability in Depressed Adolescents

Lewis

Port

Frye

et al. 2016

Front. Neural Circuits

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Introduction: Transcranial magnetic stimulation (TMS) research has suggested dysfunction in cortical glutamatergic systems in adolescent depression, while proton magnetic resonance spectroscopy (1H-MRS) studies have demonstrated deficits in concentrations of glutamatergic metabolites in depressed individuals in several cortical regions, including the anterior cingulate cortex (ACC). However, few studies have combined TMS and MRS methods to examine relationships between glutamatergic neurochemistry and excitatory and inhibitory neural functions, and none have utilized TMS-MRS methodology in clinical populations or in youth. This exploratory study aimed to examine relationships between TMS measures of cortical excitability and inhibition and concentrations of glutamatergic metabolites as measured by 1H-MRS in depressed adolescents.Methods: Twenty-four adolescents (aged 11–18 years) with depressive symptoms underwent TMS testing, which included measures of the resting motor threshold (RMT), cortical silent period (CSP), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF). Fourteen participants from the same sample also completed 1H-MRS in a 3 T MRI scanner after TMS testing. Glutamate + glutamine (Glx) concentrations were measured in medial ACC and left primary motor cortex voxels with a TE-optimized PRESS sequence. Metabolite concentrations were corrected for cerebrospinal fluid (CSF) after tissue segmentation. Pearson product-moment and Spearman rank-order correlations were calculated to assess relationships between TMS measures and [Glx].Results: In the left primary motor cortex voxel, [Glx] had a significant positive correlation with the RMT. In the medial ACC voxel, [Glx] had significant positive correlations with ICF at the 10-ms and 20-ms interstimulus intervals (ISIs).Conclusion: These preliminary data implicate glutamate in cortical excitatory processes measured by TMS. Limitations included small sample size, lack of healthy control comparators, possible age- and sex-related effects, and observational nature of the study. Further research aimed at examining the relationship between glutamatergic metabolite concentrations measured through MRS and the excitatory and inhibitory physiology measured through TMS is warranted. Combined TMS-MRS methods show promise for future investigations of the pathophysiology of depression in adults as well as in children and adolescents.

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“…It should be noted that the fluid matrix [hence the aqueous extracellular matrix (ECM)] forming the internal medium is the product of the organism itself and it can play a basic role in the intercellular communication processes (27–30). The evidence that the internal medium and in particular the ECM is produced by the organism according to its functional needs implies a broader view of homeostasis, since the self-construction of the internal medium is in some way related to concepts introduced in the 1970s by Varela et al (31) and discussed by others by stating (31–33): 'A living system is a system capable of self-reproduction and self-maintenance through a regenerative network of processes which take place within a boundary of its own making and regenerates itself through cognitive or adaptive interactions with the medium' (33).…”

Section: Historical Aspectsmentioning

confidence: 99%

Homeostasis and the concept of 'interstitial fluids hierarchy': Relevance of cerebrospinal fluid sodium concentrations and brain temperature control (Review)

Agnati

Marcoli

Leo

et al. 2017

International Journal of Molecular Medicine

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In this review, the aspects and further developments of the concept of homeostasis are discussed also in the perspective of their possible impact in the clinical practice, particularly as far as psychic homeostasis is concerned. A brief historical survey and comments on the concept of homeostasis and allostasis are presented to introduce our proposal that is based on the classical assumption of the interstitial fluid (ISF) as the internal medium for multicellular organisms. However, the new concept of a hierarchic role of ISF of the various organs is introduced. Additionally, it is suggested that particularly for some chemico-physical parameters, oscillatory rhythms within their proper set-ranges should be considered a fundamental component of homeostasis. Against this background, we propose that the brain ISF has the highest hierarchic role in human beings, providing the optimal environment, not simply for brain cell survival, but also for brain complex functions and the oscillatory rhythms of some parameters, such as cerebrospinal fluid sodium and brain ISF pressure waves, which may play a crucial role in brain physio-pathological states. Thus, according to this proposal, the brain ISF represents the real internal medium since the maintenance of its dynamic intra-set-range homeostasis is the main factor for a free and independent life of higher vertebrates. Furthermore, the evolutionary links between brain and kidney and their synergistic role in H2O/Na balance and brain temperature control are discussed. Finally, it is surmised that these two interrelated parameters have deep effects on the Central Nervous System (CNS) higher integrative actions such those linked to psychic homeostasis.

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On the role of the extracellular space on the holistic behavior of the brain

Cited by 37 publications

References 130 publications

Long-term retention of ECM hydrogel after implantation into a sub-acute stroke cavity reduces lesion volume

Long-term retention of ECM hydrogel after implantation into a sub-acute stroke cavity reduces lesion volume

An Exploratory Study of Spectroscopic Glutamatergic Correlates of Cortical Excitability in Depressed Adolescents

Homeostasis and the concept of 'interstitial fluids hierarchy': Relevance of cerebrospinal fluid sodium concentrations and brain temperature control (Review)

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