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1.
Learn Mem ; 27(6): 222-235, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32414940

RESUMO

Perineuronal nets (PNNs) are specialized extracellular matrix structures that surround subsets of neurons throughout the central nervous system (CNS). They are made up of chondroitin sulfate proteoglycans (CSPGs), hyaluronan, tenascin-R, and many other link proteins that together make up their rigid and lattice-like structure. Modulation of PNNs can alter synaptic plasticity and thereby affect learning, memory, and cognition. In the present study, we degraded PNNs in the medial prefrontal (mPFC) and posterior parietal (PPC) cortices of Long-Evans rats using the enzyme chondroitinase ABC (ChABC), which cleaves apart CSPGs. We then measured the consequences of PNN degradation on spatial working memory (WM) with a trial-unique, non-matching-to location (TUNL) automated touchscreen task. All rats were trained with a standard 6 sec delay and 20 sec inter-trial interval (ITI) and then tested under four different conditions: a 6 sec delay, a variable 2 or 6 sec delay, a 2 sec delay with a 1 sec ITI (interference condition), and a 20 sec delay. Rats that received mPFC ChABC treatment initially performed TUNL with higher accuracy, more selection trials completed, and fewer correction trials completed compared to controls in the 20 sec delay condition but did not perform differently from controls in any other condition. Rats that received PPC ChABC treatment did not perform significantly differently from controls in any condition. Posthumous immunohistochemistry confirmed an increase in CSPG degradation products (C4S stain) in the mPFC and PPC following ChABC infusions while WFA staining intensity and parvalbumin positive neuron number were decreased following mPFC, but not PPC, ChABC infusions. These findings suggest that PNNs in the mPFC play a subtle role in spatial WM, but PNNs in the PPC do not. Furthermore, it appears that PNNs in the mPFC are involved in adapting to a challenging novel delay, but that they do not play an essential role in spatial WM function.


Assuntos
Condroitina ABC Liase/farmacologia , Proteoglicanas de Sulfatos de Condroitina/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Lobo Parietal/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Masculino , Ratos , Ratos Long-Evans , Fatores de Tempo
2.
Can J Psychiatry ; 64(1): 5-17, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29742910

RESUMO

Schizophrenia is a heterogeneous psychiatric disorder that is poorly treated with current therapies. In this brief review, we provide an update regarding the use of animal models to study schizophrenia in an attempt to understand its aetiology and develop novel therapeutic strategies. Tremendous progress has been made developing and validating rodent models that replicate the aetiologies, brain pathologies, and behavioural abnormalities associated with schizophrenia in humans. Here, models are grouped into 3 categories-developmental, drug induced, and genetic-to reflect the heterogeneous risk factors associated with schizophrenia. Each of these models is associated with varied but overlapping pathophysiology, endophenotypes, behavioural abnormalities, and cognitive impairments. Studying schizophrenia using multiple models will permit an understanding of the core features of the disease, thereby facilitating preclinical research aimed at the development and validation of better pharmacotherapies to alter the progression of schizophrenia or alleviate its debilitating symptoms.


Assuntos
Modelos Animais de Doenças , Esquizofrenia/etiologia , Animais , Esquizofrenia/patologia , Esquizofrenia/fisiopatologia , Esquizofrenia/terapia
3.
J Neurosci ; 37(45): 10983-10997, 2017 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-29025926

RESUMO

The limited recovery that occurs following stroke happens almost entirely in the first weeks postinjury. Moreover, the efficacy of rehabilitative training is limited beyond this narrow time frame. Sprouting of spared corticospinal tract axons in the contralesional spinal cord makes a significant contribution to sensorimotor recovery, but this structural plasticity is also limited to the first few weeks after stroke. Here, we tested the hypothesis that inducing plasticity in the spinal cord during chronic stroke could improve recovery from persistent sensorimotor impairment. We potentiated spinal plasticity during chronic stroke, weeks after the initial ischemic injury, in male Sprague-Dawley rats via intraspinal injections of chondroitinase ABC. Our data show that chondroitinase injections into the contralesional gray matter of the cervical spinal cord administered 28 d after stroke induced significant sprouting of corticospinal axons originating in the peri-infarct cortex. Chondroitinase ABC injection during chronic stroke without additional training resulted in moderate improvements of sensorimotor deficits. Importantly, this therapy dramatically potentiated the efficacy of rehabilitative training delivered during chronic stroke in a skilled forelimb reaching task. These novel data suggest that spinal therapy during chronic stroke can amplify the benefits of delayed rehabilitative training with the potential to reduce permanent disability in stroke survivors.SIGNIFICANCE STATEMENT The brain and spinal cord undergo adaptive rewiring ("plasticity") following stroke. This plasticity allows for partial functional recovery from stroke induced sensorimotor impairments. However, the plasticity that underlies recovery occurs predominantly in the first weeks following stroke, and most stroke survivors are left with permanent disability even after rehabilitation. Using animal models, our data show that removal of plasticity-inhibiting signals in the spinal cord (via intraspinal injections of the enzyme chondroitinase ABC) augments rewiring of circuits connecting the brain to the spinal cord, even weeks after stroke. Moreover, this plasticity can be harnessed by rehabilitative training to significantly promote sensorimotor recovery. Thus, intraspinal therapy may augment rehabilitative training and improve recovery even in individuals living with chronic disability due to stroke.


Assuntos
Condroitina ABC Liase/uso terapêutico , Plasticidade Neuronal , Recuperação de Função Fisiológica , Medula Espinal/fisiopatologia , Reabilitação do Acidente Vascular Cerebral , Animais , Condroitina ABC Liase/administração & dosagem , Membro Anterior/fisiopatologia , Substância Cinzenta , Injeções Espinhais , Masculino , Destreza Motora , Regeneração Nervosa/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Sensação , Acidente Vascular Cerebral/fisiopatologia
4.
Microcirculation ; 22(3): 228-36, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25351102

RESUMO

Cerebral collaterals are vascular redundancies in the cerebral circulation that can partially maintain blood flow to ischemic tissue when primary conduits are blocked. After occlusion of a cerebral artery, anastomoses connecting the distal segments of the MCA with distal branches of the ACA and PCA (known as leptomeningeal or pial collaterals) allow for partially maintained blood flow in the ischemic penumbra and delay or prevent cell death. However, collateral circulation varies dramatically between individuals, and collateral extent is significant predictor of stroke severity and recanalization rate. Collateral therapeutics attempt to harness these vascular redundancies by enhancing blood flow through pial collaterals to reduce ischemia and brain damage after cerebral arterial occlusion. While therapies to enhance collateral flow remain relatively nascent neuroprotective strategies, experimental therapies including inhaled NO, transient suprarenal aortic occlusion, and electrical stimulation of the parasympathetic sphenopalatine ganglion show promise as collateral therapeutics with the potential to improve treatment of acute ischemic stroke.


Assuntos
Circulação Cerebrovascular , Infarto da Artéria Cerebral Média , Doença Aguda , Animais , Velocidade do Fluxo Sanguíneo , Terapia por Estimulação Elétrica/métodos , Humanos , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Infarto da Artéria Cerebral Média/fisiopatologia , Infarto da Artéria Cerebral Média/terapia , Fármacos Neuroprotetores/uso terapêutico , Radiografia
5.
J Neurophysiol ; 111(1): 145-63, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24068759

RESUMO

Spinal cord transection leads to elimination of brain stem-derived monoamine fibers that normally synthesize most of the monoamines in the spinal cord, including serotonin (5-hydroxytryptamine, 5-HT) synthesized from tryptophan by enzymes tryptophan hydroxylase (TPH, synthesizing 5-hydroxytryptophan, 5-HTP) and aromatic l-amino acid decarboxylase (AADC, synthesizing 5-HT from 5-HTP). Here we examine whether spinal cord caudal to transection remains able to manufacture and metabolize 5-HT. Immunolabeling for AADC reveals that, while most AADC is confined to brain stem-derived monoamine fibers in spinal cords from normal rats, caudal to transection AADC is primarily found in blood vessel endothelial cells and pericytes as well as a novel group of neurons (NeuN positive and GFAP negative), all of which strongly upregulate AADC with injury. However, immunolabeling for 5-HT reveals that there is no detectable endogenous 5-HT synthesis in any structure in the spinal cord caudal to a chronic transection, including in AADC-containing vessels and neurons, consistent with a lack of TPH. In contrast, when we applied exogenous 5-HTP (in vitro or in vivo), AADC-containing vessels and neurons synthesized 5-HT, which contributed to increased motoneuron activity and muscle spasms (long-lasting reflexes, LLRs), by acting on 5-HT2 receptors (SB206553 sensitive) located on motoneurons (TTX resistant). Blocking monoamine oxidase (MAO) markedly increased the sensitivity of the motoneurons (LLR) to 5-HTP, more than it increased the sensitivity of motoneurons to 5-HT, suggesting that 5-HT synthesized from AADC is largely metabolized in AADC-containing neurons and vessels. In summary, after spinal cord injury AADC is upregulated in vessels, pericytes, and neurons but does not endogenously produce 5-HT, whereas when exogenous 5-HTP is provided AADC does produce functional amounts of 5-HT, some of which is able to escape metabolism by MAO, diffuse out of these AADC-containing cells, and ultimately act on 5-HT receptors on motoneurons.


Assuntos
Descarboxilases de Aminoácido-L-Aromático/metabolismo , Serotonina/biossíntese , Traumatismos da Medula Espinal/metabolismo , Medula Espinal/metabolismo , Animais , Descarboxilases de Aminoácido-L-Aromático/genética , Tronco Encefálico/metabolismo , Feminino , Neurônios Motores/metabolismo , Especificidade de Órgãos , Pericitos/metabolismo , Ratos , Serotonina/metabolismo , Serotonina/farmacologia , Medula Espinal/citologia , Medula Espinal/efeitos dos fármacos
7.
Front Psychiatry ; 15: 1386321, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38807690

RESUMO

Intense interest surrounds current research on psychedelics, particularly regarding their potential in treating mental health disorders. Various studies suggest a link between the subjective effects produced by psychedelics and their therapeutic efficacy. Neuroimaging evidence indicates an association of changes in brain functional connectivity with the subjective effects of psychedelics. We conducted a review focusing on psychedelics and brain functional connectivity. The review focused on four psychedelic drugs: ayahuasca, psilocybin and LSD, and the entactogen MDMA. We conducted searches in databases of MEDLINE, Embase, APA PsycInfo and Scopus from inception to Jun 2023 by keywords related to functional connectivity and psychedelics. Using the PRISMA framework, we selected 24 articles from an initial pool of 492 for analysis. This scoping review and analysis investigated the effects of psychedelics on subjective experiences and brain functional connectivity in healthy individuals. The studies quantified subjective effects through psychometric scales, revealing significant experiences of altered consciousness, mood elevation, and mystical experiences induced by psychedelics. Neuroimaging results indicated alterations in the functional connectivity of psychedelics, with consistent findings across substances of decreased connectivity within the default mode network and increased sensory and thalamocortical connectivity. Correlations between these neurophysiological changes and subjective experiences were noted, suggesting a brain network basis of the psychedelics' neuropsychological impact. While the result of the review provides a potential neural mechanism of the subjective effects of psychedelics, direct clinical evidence is needed to advance their clinical outcomes. Our research serves as a foundation for further exploration of the therapeutic potential of psychedelics.

8.
Neurosci Insights ; 18: 26331055231186993, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37465214

RESUMO

Chondroitin sulfate proteoglycans (CSPGs), one of the major extracellular matrix components of the glial scar that surrounds central nervous system (CNS) injuries, are known to inhibit the regeneration of neurons. This study investigated whether pleiotrophin (PTN), a growth factor upregulated during early CNS development, can overcome the inhibition mediated by CSPGs and promote the neurite outgrowth of neurons in vitro. The data showed that a CSPG matrix inhibited the outgrowth of neurites in primary cortical neuron cultures compared to a control matrix. PTN elicited a dose-dependent increase in the neurite outgrowth even in the presence of the growth inhibitory CSPG matrix, with optimal growth at 15 ng mL-1 of PTN (114.8% of neuronal outgrowth relative to laminin control). The growth-promoting effect of PTN was blocked by inhibition of the receptor anaplastic lymphoma kinase (ALK) by alectinib in a dose-dependent manner. Neurite outgrowth in the presence of this CSPG matrix was induced by activation of the protein kinase B (AKT) pathway, a key downstream mediator of ALK activation. This study identified PTN as a dose-dependent regulator of neurite outgrowth in primary cortical neurons cultured in the presence of a CSPG matrix and identified ALK activation as a key driver of PTN-induced growth.

9.
Front Aging Neurosci ; 14: 1041333, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36620775

RESUMO

Stroke is among the leading causes of death and disability worldwide. Restoring blood flow through recanalization is currently the only acute treatment for cerebral ischemia. Unfortunately, many patients that achieve a complete recanalization fail to regain functional independence. Recent studies indicate that activation of peripheral immune cells, particularly neutrophils, may contribute to microcirculatory failure and futile recanalization. Stroke primarily affects the elderly population, and mortality after endovascular therapies is associated with advanced age. Previous analyses of differential gene expression across injury status and age identify ischemic stroke as a complex age-related disease. It also suggests robust interactions between stroke injury, aging, and inflammation on a cellular and molecular level. Understanding such interactions is crucial in developing effective protective treatments. The global stroke burden will continue to increase with a rapidly aging human population. Unfortunately, the mechanisms of age-dependent vulnerability are poorly defined. In this review, we will discuss how neutrophil-specific gene expression patterns may contribute to poor treatment responses in stroke patients. We will also discuss age-related transcriptional changes that may contribute to poor clinical outcomes and greater susceptibility to cerebrovascular diseases.

10.
PLoS One ; 16(4): e0236684, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33914738

RESUMO

Artificial forms of mechanical limb stimulation are used within multiple fields of study to determine the level of cortical excitability and to map the trajectory of neuronal recovery from cortical damage or disease. Square-wave mechanical or electrical stimuli are often used in these studies, but a characterization of sensory-evoked response properties to square-waves with distinct fundamental frequencies but overlapping harmonics has not been performed. To distinguish between somatic stimuli, the primary somatosensory cortex must be able to represent distinct stimuli with unique patterns of activity, even if they have overlapping features. Thus, mechanical square-wave stimulation was used in conjunction with regional and cellular imaging to examine regional and cellular response properties evoked by different frequencies of stimulation. Flavoprotein autofluorescence imaging was used to map the somatosensory cortex of anaesthetized C57BL/6 mice, and in vivo two-photon Ca2+ imaging was used to define patterns of neuronal activation during mechanical square-wave stimulation of the contralateral forelimb or hindlimb at various frequencies (3, 10, 100, 200, and 300 Hz). The data revealed that neurons within the limb associated somatosensory cortex responding to various frequencies of square-wave stimuli exhibit stimulus-specific patterns of activity. Subsets of neurons were found to have sensory-evoked activity that is either primarily responsive to single stimulus frequencies or broadly responsive to multiple frequencies of limb stimulation. High frequency stimuli were shown to elicit more population activity, with a greater percentage of the population responding and greater percentage of cells with high amplitude responses. Stimulus-evoked cell-cell correlations within these neuronal networks varied as a function of frequency of stimulation, such that each stimulus elicited a distinct pattern that was more consistent across multiple trials of the same stimulus compared to trials at different frequencies of stimulation. The variation in cortical response to different square-wave stimuli can thus be represented by the population pattern of supra-threshold Ca2+ transients, the magnitude and temporal properties of the evoked activity, and the structure of the stimulus-evoked correlation between neurons.


Assuntos
Rede Nervosa/fisiologia , Neurônios/fisiologia , Córtex Somatossensorial/fisiologia , Animais , Cálcio/metabolismo , Estimulação Elétrica , Potenciais Somatossensoriais Evocados , Membro Anterior/fisiologia , Membro Posterior/fisiologia , Masculino , Camundongos Endogâmicos C57BL
11.
Front Neurol ; 12: 746486, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34956045

RESUMO

Remote ischemic conditioning (RIC), which involves a series of short cycles of ischemia in an organ remote to the brain (typically the limbs), has been shown to protect the ischemic penumbra after stroke and reduce ischemia/reperfusion (IR) injury. Although the exact mechanism by which this protective signal is transferred from the remote site to the brain remains unclear, preclinical studies suggest that the mechanisms of RIC involve a combination of circulating humoral factors and neuronal signals. An improved understanding of these mechanisms will facilitate translation to more effective treatment strategies in clinical settings. In this review, we will discuss potential protective mechanisms in the brain and cerebral vasculature associated with RIC. We will discuss a putative role of the immune system and circulating mediators of inflammation in these protective processes, including the expression of pro-and anti-inflammatory genes in peripheral immune cells that may influence the outcome. We will also review the potential role of extracellular vesicles (EVs), biological vectors capable of delivering cell-specific cargo such as proteins and miRNAs to cells, in modulating the protective effects of RIC in the brain and vasculature.

12.
Front Cell Neurosci ; 15: 634020, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33889075

RESUMO

Microglia are the primary cells in the central nervous system that identify and respond to injury or damage. Such a perturbation in the nervous system induces the release of molecules including ATP and glutamate that act as damage-associated molecular patterns (DAMPs). DAMPs are detected by microglia, which then regulate the inflammatory response in a manner sensitive to their surrounding environment. The available data indicates that ATP and glutamate can induce the release of pro inflammatory factors TNF (tumor necrosis factor), IL-1ß (interleukin 1 beta), and NO (nitric oxide) from microglia. However, non-physiological concentrations of ATP and glutamate were often used to derive these insights. Here, we have compared the response of spinal cord microglia (SM) relative to brain microglia (BM) using physiologically relevant concentrations of glutamate and ATP that mimic injured conditions in the central nervous system. The data show that ATP and glutamate are not significant modulators of the release of cytokines from either BM or SM. Consistent with previous studies, spinal microglia exhibited a general trend toward reduced release of inflammatory cytokines relative to brain-derived microglia. Moreover, we demonstrate that the responses of microglia to these DAMPs can be altered by modifying the biochemical milieu in their surrounding environment. Preconditioning brain derived microglia with media from spinal cord derived mixed glial cultures shifted their release of IL-1ß and IL-6 to a less inflammatory phenotype consistent with spinal microglia.

13.
Neurology ; 97(21): e2079-e2087, 2021 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-34607925

RESUMO

BACKGROUND AND OBJECTIVES: The rate of infarct core progression in patients with acute ischemic stroke is variable and affects outcome of reperfusion therapy. We evaluated the hypoperfusion index (HI) to estimate the initial rate of core progression in patients with medium vessel occlusion (MeVO) compared to large vessel occlusion (LVO) stroke and within a larger time frame since stroke onset. METHODS: Core progression was assessed in 106 patients with acute stroke and CT perfusion. Using reperfusion trial core time criteria, fast progressors had core >70 mL within 6 hours of stroke onset and slow progressors had core ≤70 mL, mismatch ≥15 mL, and mismatch to core ratio ≥1.8 within 6 to 24 hours. The relationship between HI and infarct core progression (core/time) was examined using receiver operating characteristics to determine optimal HI cutoff. The HI cutoff was then tested in the overall cohort, compared between MeVO and LVO, and evaluated in patients up to 24 hours from stroke onset to differentiate fast from slow rate of core progression. HI threshold was assessed in a second independent cohort of 110 patients with acute ischemic stroke. RESULTS: In 106 patients with acute stroke, 6.6% were fast progressors, 27.4% were slow progressors, and 66% were not classified as fast or slow progressor by reperfusion trial core time criteria. HI >0.5 was associated with fast progression and able to distinguish fast from slow progressors (area under the curve [AUC] 0.94; 95% confidence interval [CI] 0.80-0.99). In MeVO (n = 26) HI >0.5 had a core progression of 0.30 mL/min compared to 0.03 mL/min for HI ≤0.5 (p < 0.001). In LVO (n = 80), HI >0.5 had a core progression of 0.26 mL/min compared to 0.02 mL/min for HI ≤0.5 (p < 0.001). In patients not classified as fast or slow progressor by reperfusion trial criteria, those with HI >0.5 had progression rate of 0.21 mL/min compared to 0.03 mL/min for those with HI ≤0.5 (p < 0.001). Validation in a second cohort of patients with acute ischemic stroke (n = 110; MeVO = 42, LVO = 68) yielded similar results for HI >0.5 to distinguish fast and slow core progression with an AUC of 0.84 (95% CI 0.72-0.97). DISCUSSION: HI can differentiate fast from slow core progression in MeVO and LVO within the first 24 hours of acute ischemic stroke. Consideration of core progression rate at time of stroke evaluation may have implications in the selection of patients with MeVO and LVO stroke for reperfusion therapy that warrant further study.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/terapia , Progressão da Doença , Humanos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/terapia , Tomografia Computadorizada por Raios X
14.
J Neurosci ; 29(6): 1719-34, 2009 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-19211879

RESUMO

After brain damage such as stroke, topographically organized sensory and motor cortical representations remap onto adjacent surviving tissues. It is conceivable that cortical remapping is accomplished by changes in the temporal precision of sensory processing and regional connectivity in the cortex. To understand how the adult cortex remaps and processes sensory signals during stroke recovery, we performed in vivo imaging of sensory-evoked changes in membrane potential, as well as multiphoton imaging of dendrite structure and tract tracing. In control mice, forelimb stimulation evoked a brief depolarization in forelimb cortex that quickly propagated to, and dissipated within, adjacent motor/hindlimb areas (<100 ms). One week after forelimb cortex stroke, the cortex was virtually unresponsive to tactile forelimb stimulation. After 8 weeks recovery, forelimb-evoked depolarizations reemerged with a characteristic pattern in which responses began within surviving portions of forelimb cortex (<20 ms after stimulation) and then spread horizontally into neighboring peri-infarct motor/hindlimb areas in which depolarization persisted 300-400% longer than controls. These uncharacteristically prolonged responses were not limited to the remapped peri-infarct zone and included distant posteromedial retrosplenial cortex, millimeters from the stroke. Structurally, the remapped peri-infarct area selectively exhibited high levels of dendritic spine turnover, shared more connections with retrosplenial cortex and striatum, and lost inputs from lateral somatosensory cortical regions. Our findings demonstrate that sensory remapping during stroke recovery is accompanied by the development of prolonged sensory responses and new structural circuits in both the peri-infarct zone as well as more distant sites.


Assuntos
Mapeamento Encefálico , Infarto Cerebral/diagnóstico , Corantes Fluorescentes , Rede Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Rosa Bengala , Córtex Somatossensorial/anatomia & histologia , Córtex Somatossensorial/fisiologia , Animais , Mapeamento Encefálico/métodos , Infarto Cerebral/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Rede Nervosa/química , Rede Nervosa/fisiopatologia , Estimulação Luminosa/métodos , Córtex Somatossensorial/química , Fatores de Tempo
15.
Transl Stroke Res ; 11(2): 243-253, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31203565

RESUMO

Cerebral collateral circulation and age are critical factors in determining outcome from acute ischemic stroke. Aging may lead to rarefaction of cerebral collaterals, and thereby accelerate ischemic injury by reducing penumbral blood flow. Dynamic changes in pial collaterals after onset of cerebral ischemia may vary with age but have not been extensively studied. Here, laser speckle contrast imaging (LSCI) and two-photon laser scanning microscopy (TPLSM) were combined to monitor cerebral pial collaterals between the anterior cerebral artery (ACA) and the middle cerebral artery (MCA) in young adult and aged male Sprague Dawley rats during distal middle cerebral artery occlusion (dMCAo). Histological analysis showed that aged rats had significantly greater volumes of ischemic damage than young rats. LSCI showed that cerebral collateral perfusion declined over time after stroke in aged and young rats, and that this decline was significantly greater in aged rats. TPLSM demonstrated that pial arterioles narrowed faster after dMCAo in aged rats compared to young adult rats. Notably, while arteriole vessel narrowing was comparable 4.5 h after ischemic onset in aged and young adult rats, red blood cell velocity was stable in young adults but declined over time in aged rats. Overall, red blood cell flux through pial arterioles was significantly reduced at all time-points after 90 min post-dMCAo in aged rats relative to young adult rats. Thus, collateral failure is more severe in aged rats with significantly impaired pial collateral dynamics (reduced diameter, red blood cell velocity, and red blood cell flux) relative to young adult rats.


Assuntos
Envelhecimento/fisiologia , Isquemia Encefálica/fisiopatologia , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/fisiopatologia , AVC Isquêmico/fisiopatologia , Animais , Artéria Cerebral Anterior/patologia , Artéria Cerebral Anterior/fisiopatologia , Arteríolas/diagnóstico por imagem , Arteríolas/patologia , Arteríolas/fisiopatologia , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/patologia , Córtex Cerebral/patologia , AVC Isquêmico/diagnóstico por imagem , AVC Isquêmico/patologia , Masculino , Artéria Cerebral Média/patologia , Artéria Cerebral Média/fisiopatologia , Imagem Óptica , Ratos Sprague-Dawley
16.
Sci Rep ; 10(1): 12392, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32709950

RESUMO

Circulation through cerebral collaterals can maintain tissue viability until reperfusion is achieved. However, collateral circulation is time limited, and failure of collaterals is accelerated in the aged. Remote ischemic perconditioning (RIPerC), which involves inducing a series of repetitive, transient peripheral cycles of ischemia and reperfusion at a site remote to the brain during cerebral ischemia, may be neuroprotective and can prevent collateral failure in young adult rats. Here, we demonstrate the efficacy of RIPerC to improve blood flow through collaterals in aged (16-18 months of age) Sprague Dawley rats during a distal middle cerebral artery occlusion. Laser speckle contrast imaging and two-photon laser scanning microscopy were used to directly measure flow through collateral connections to ischemic tissue. Consistent with studies in young adult rats, RIPerC enhanced collateral flow by preventing the stroke-induced narrowing of pial arterioles during ischemia. This improved flow was associated with reduced early ischemic damage in RIPerC treated aged rats relative to controls. Thus, RIPerC is an easily administered, non-invasive neuroprotective strategy that can improve penumbral blood flow via collaterals. Enhanced collateral flow supports further investigation as an adjuvant therapy to recanalization therapy and a protective treatment to maintain tissue viability prior to reperfusion.


Assuntos
Hemodinâmica , Infarto da Artéria Cerebral Média/fisiopatologia , Infarto da Artéria Cerebral Média/terapia , Precondicionamento Isquêmico Miocárdico , Animais , Masculino , Ratos , Ratos Sprague-Dawley
17.
Sci Rep ; 10(1): 22013, 2020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33328490

RESUMO

High intracranial pressure (ICP) can impede cerebral blood flow resulting in secondary injury or death following severe stroke. Compensatory mechanisms include reduced cerebral blood and cerebrospinal fluid volumes, but these often fail to prevent raised ICP. Serendipitous observations in intracerebral hemorrhage (ICH) suggest that neurons far removed from a hematoma may shrink as an ICP compliance mechanism. Here, we sought to critically test this observation. We tracked the timing of distal tissue shrinkage (e.g. CA1) after collagenase-induced striatal ICH in rat; cell volume and density alterations (42% volume reduction, 34% density increase; p < 0.0001) were highest day one post-stroke, and rebounded over a week across brain regions. Similar effects were seen in the filament model of middle cerebral artery occlusion (22% volume reduction, 22% density increase; p ≤ 0.007), but not with the Vannucci-Rice model of hypoxic-ischemic encephalopathy (2.5% volume increase, 14% density increase; p ≥ 0.05). Concerningly, this 'tissue compliance' appears to cause sub-lethal damage, as revealed by electron microscopy after ICH. Our data challenge the long-held assumption that 'healthy' brain tissue outside the injured area maintains its volume. Given the magnitude of these effects, we posit that 'tissue compliance' is an important mechanism invoked after severe strokes.


Assuntos
Hemorragia Cerebral/patologia , Acidente Vascular Cerebral Hemorrágico/patologia , AVC Isquêmico/patologia , Modelos Biológicos , Animais , Astrócitos/patologia , Região CA1 Hipocampal/patologia , Região CA1 Hipocampal/ultraestrutura , Tamanho Celular , Masculino , Neurônios/patologia , Ratos Sprague-Dawley
18.
Brain Res ; 1740: 146860, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32353433

RESUMO

Remote ischemic perconditioning (RIPerC) results in collateral enhancement and a reduction in middle cerebral artery occlusion (MCAO) induced ischemia. RIPerC likely activates multiple metabolic protective mechanisms, including effects on matrix metalloproteinases (MMPs) and protein kinases. Here we explore if RIPerC improves neuroprotection and collateral flow by modifying the activities of MMP-9 and AMPK/e-NOS. Age matched adult male Sprague Dawley rats were subjected to MCAO followed one hour later by RIPerC (3 cycles of 15 min ischemia). Animals were euthanized 24 h post-MCAO. Haematoxylin and Eosin (H&E) staining 24 h post-MCAO revealed a significant (p < 0.02) reduction in the infarction volume in RIPerC treated animals (24.9 ± 5.4%) relative to MCAO controls (42.5 ± 4.2, %). TUNEL staining showed a 42.6% reduction in the apoptotic cells with RIPerC treatment (p < 0.01). Immunoblotting in congruence with RT-PCR and Zymography showed that RIPerC significantly reduced MMP-9 expression and activity in RIPerC + MCAO group compared to MCAO group (218.3 ± 19.1% vs. 148.9 ± 12.05% (p < 0.01). Immunoblotting revealed that RIPerC was associated with a significant 2.5-fold increase in activation of p-AMPK compared to the MCAO group (p < 0.01) which was also associated with a significant increase in the e-NOS activity (p < 0.01). RIPerC resulted in reduction of infarction volume, decreased apoptotic cell death and attenuated MMP-9 activity. This together with the increased activity of p-AMPK and increase in p-eNOS may, in part explain the neuroprotection and sustained increase in blood flow observed with RIPerC following acute stroke.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Isquemia Encefálica/metabolismo , Precondicionamento Isquêmico/métodos , Metaloproteinase 9 da Matriz/metabolismo , Neuroproteção/fisiologia , Óxido Nítrico Sintase Tipo III/metabolismo , Animais , Isquemia Encefálica/prevenção & controle , Precondicionamento Isquêmico/tendências , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia
19.
J Neurosci ; 28(26): 6592-606, 2008 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-18579732

RESUMO

Functional mapping and microstimulation studies suggest that recovery after stroke damage can be attributed to surviving brain regions taking on the functional roles of lost tissues. Although this model is well supported by data, it is not clear how activity in single neurons is altered in relation to cortical functional maps. It is conceivable that individual surviving neurons could adopt new roles at the expense of their usual function. Alternatively, neurons that contribute to recovery may take on multiple functions and exhibit a wider repertoire of neuronal processing. In vivo two-photon calcium imaging was used in adult mice within reorganized forelimb and hindlimb somatosensory functional maps to determine how the response properties of individual neurons and glia were altered during recovery from ischemic damage over a period of 2-8 weeks. Single-cell calcium imaging revealed that the limb selectivity of individual neurons was altered during recovery from ischemia, such that neurons normally selective for a single contralateral limb processed information from multiple limbs. Altered limb selectivity was most prominent in border regions between stroke-altered forelimb and hindlimb macroscopic map representations, and peaked 1 month after the targeted insult. Two months after stroke, individual neurons near the center of reorganized functional areas became more selective for a preferred limb. These previously unreported forms of plasticity indicate that in adult animals, seemingly hardwired cortical neurons first adopt wider functional roles as they develop strategies to compensate for loss of specific sensory modalities after forms of brain damage such as stroke.


Assuntos
Sinalização do Cálcio , Regeneração Nervosa , Plasticidade Neuronal , Neurônios/metabolismo , Córtex Somatossensorial , Acidente Vascular Cerebral/fisiopatologia , Adaptação Fisiológica , Vias Aferentes , Animais , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Mapeamento Encefálico , Extremidades/inervação , Lateralidade Funcional , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/patologia , Neurônios Aferentes/metabolismo , Neurônios Aferentes/patologia , Óptica e Fotônica , Estimulação Luminosa , Recuperação de Função Fisiológica , Córtex Somatossensorial/patologia , Coloração e Rotulagem , Acidente Vascular Cerebral/metabolismo
20.
J Neurosci ; 27(23): 6268-72, 2007 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-17554000

RESUMO

Elevation of intracellular Ca2+ in astrocytes can influence cerebral microcirculation and modulate synaptic transmission. Recently, in vivo imaging studies identified delayed, sensory-driven Ca2+ oscillations in cortical astrocytes; however, the long latencies of these Ca2+ signals raises questions in regards to their suitability for a role in short-latency modulation of cerebral microcirculation or rapid astrocyte-to-neuron communication. Here, using in vivo two-photon Ca2+ imaging, we demonstrate that approximately 5% of sulforhodamine 101-labeled astrocytes in the hindlimb area of the mouse primary somatosensory cortex exhibit short-latency (peak amplitude approximately 0.5 s after stimulus onset), contralateral hindlimb-selective sensory-evoked Ca2+ signals that operate on a time scale similar to neuronal activity and correlate with the onset of the hemodynamic response as measured by intrinsic signal imaging. The kinetics of astrocyte Ca2+ transients were similar in rise and decay times to postsynaptic neuronal transients, but decayed more slowly than neuropil Ca2+ transients that presumably reflect presynaptic transients. These in vivo findings suggest that astrocytes can respond to sensory activity in a selective manner and process information on a subsecond time scale, enabling them to potentially form an active partnership with neurons for rapid regulation of microvascular tone and neuron-astrocyte network properties.


Assuntos
Astrócitos/fisiologia , Sinalização do Cálcio/fisiologia , Neurônios/fisiologia , Córtex Somatossensorial/irrigação sanguínea , Córtex Somatossensorial/fisiologia , Potenciais de Ação/fisiologia , Animais , Feminino , Membro Posterior/irrigação sanguínea , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microcirculação/fisiologia , Fatores de Tempo
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