Michael Nilsson

Astrocyte activation and reactive gliosis

Astrocytes become activated (reactive) in response to many CNS pathologies, such as stroke, trauma, growth of a tumor, or neurodegenerative disease. The process of astrocyte activation remains rather enigmatic and results in so‐called “reactive gliosis,” a reaction with specific structural and functional characteristics. In stroke or in CNS trauma, the lesion itself, the ischemic environment, disrupted blood‐brain barrier, the inflammatory response, as well as in metabolic, excitotoxic, and in some cases oxidative crises—all affect the extent and quality of reactive gliosis. The fact that astrocytes function as a syncytium of interconnected cells both in health and in disease, rather than as individual cells, adds yet another dimension to this picture. This review focuses on several aspects of astrocyte activation and reactive gliosis and discusses its possible roles in the CNS trauma and ischemia. Particular emphasis is placed on the lessons learnt from mouse genetic models in which the absence of intermediate filament proteins in astrocytes leads to attenuation of reactive gliosis with distinct pathophysiological and clinical consequences.

Enriched environment increases neurogenesis in the adult rat dentate gyrus and improves spatial memory.

The fetal and even the young brain possesses a considerable degree of plasticity. The plasticity and rate of neurogenesis in the adult brain is much less pronounced. The present study was conducted to investigate whether housing conditions affect neurogenesis, learning, and memory in adult rats. Three-month-old rats housed either in isolation or in an enriched environment were injected intraperitoneally with bromodeoxyuridine (BrdU) to detect proliferation among progenitor cells and to follow their fate in the dentate gyrus. The rats were sacrificed either 1 day or 4 weeks after BrdU injections. This experimental paradigm allows for discrimination between proliferative effects and survival effects on the newborn progenitors elicited by different housing conditions. The number of newborn cells in the dentate gyrus was not altered 1 day after BrdU injections. In contrast, the number of surviving progenitors 1 month after BrdU injections was markedly increased in animals housed in an enriched environment. The relative ratio of neurogenesis and gliogenesis was not affected by environmental conditions, as estimated by double-labeling immunofluorescence staining with antibodies against BrdU and either the neuronal marker calbindin D28k or the glial marker GFAp, resulting in a net increase in neurogenesis in animals housed in an enriched environment. Furthermore, we show that adult rats housed in an enriched environment show improved performance in a spatial learning test. The results suggest that environmental cues can enhance neurogenesis in the adult hippocampal region, which is associated with improved spatial memory.

Protective role of reactive astrocytes in brain ischemia

Reactive astrocytes are thought to protect the penumbra during brain ischemia, but direct evidence has been lacking due to the absence of suitable experimental models. Previously, we generated mice deficient in two intermediate filament (IF) proteins, glial fibrillary acidic protein (GFAP) and vimentin, whose upregulation is the hallmark of reactive astrocytes. GFAP−/−Vim−/− mice exhibit attenuated posttraumatic reactive gliosis, improved integration of neural grafts, and posttraumatic regeneration. Seven days after middle cerebral artery (MCA) transection, infarct volume was 210 to 350% higher in GFAP−/−Vim−/− than in wild-type (WT) mice; GFAP−/−, Vim−/− and WT mice had the same infarct volume. Endothelin B receptor (ETBR) immunoreactivity was strong on cultured astrocytes and reactive astrocytes around infarct in WT mice but undetectable in GFAP−/−Vim−/− astrocytes. In WT astrocytes, ETBR colocalized extensively with bundles of IFs. GFAP−/−Vim−/− astrocytes showed attenuated endothelin-3-induced blockage of gap junctions. Total and glutamate transporter-1 (GLT-1)-mediated glutamate transport was lower in GFAP−/−Vim−/− than in WT mice. DNA array analysis and quantitative real-time PCR showed downregulation of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of tissue plasminogen activator. Thus, reactive astrocytes have a protective role in brain ischemia, and the absence of astrocyte IFs is linked to changes in glutamate transport, ETBR-mediated control of gap junctions, and PAI-1 expression.

Insulin-like growth factor-I and neurogenesis in the adult mammalian brain.

In most brain regions of highly developed mammals, the majority of neurogenesis is terminated soon after birth. However, new neurons are continually generated throughout life in the subventricular zone and the dentate gyrus of the hippocampus. Insulin-like growth factor-I (IGF-I) is a polypeptide hormone that has demonstrated effects on these progenitor cells. IGF-I induces proliferation of isolated progenitors in culture, as well as affecting various aspects of neuronal induction and maturation. Moreover, systemic infusion of IGF-I increases both proliferation and neurogenesis in the adult rat hippocampus, and uptake of serum IGF-I by the brain parenchyma mediates the increase in neurogenesis induced by exercise. Neurogenesis in the adult brain is regulated by many factors including aging, chronic stress, depression and brain injury. Aging is associated with reductions in both hippocampal neurogenesis and IGF-I levels, and administration of IGF-I to old rats increases neurogenesis and reverses cognitive impairments. Similarly, stress and depression also inhibit neurogenesis, possibly via the associated reductions in serotonin or increases in circulating glucocorticoids. As both of these changes have the potential to down regulate IGF-I production by neural cells, stress may inhibit neurogenesis indirectly via downregulation of IGF-I. In contrast, brain injury stimulates neurogenesis, and is associated with upregulation of IGF-I in the brain. Thus, there is a tight correlation between IGF-I and neurogenesis in the adult brain under different conditions. Further studies are needed to clarify whether IGF-I does indeed mediate neurogenesis in these situations.

Cardiovascular fitness is associated with cognition in young adulthood

During early adulthood, a phase in which the central nervous system displays considerable plasticity and in which important cognitive traits are shaped, the effects of exercise on cognition remain poorly understood. We performed a cohort study of all Swedish men born in 1950 through 1976 who were enlisted for military service at age 18 (N = 1,221,727). Of these, 268,496 were full-sibling pairs, 3,147 twin pairs, and 1,432 monozygotic twin pairs. Physical fitness and intelligence performance data were collected during conscription examinations and linked with other national databases for information on school achievement, socioeconomic status, and sibship. Relationships between cardiovascular fitness and intelligence at age 18 were evaluated by linear models in the total cohort and in subgroups of full-sibling pairs and twin pairs. Cardiovascular fitness, as measured by ergometer cycling, positively associated with intelligence after adjusting for relevant confounders (regression coefficient b = 0.172; 95% CI, 0.168–0.176). Similar results were obtained within monozygotic twin pairs. In contrast, muscle strength was not associated with cognitive performance. Cross-twin cross-trait analyses showed that the associations were primarily explained by individual specific, non-shared environmental influences (≥80%), whereas heritability explained <15% of covariation. Cardiovascular fitness changes between age 15 and 18 y predicted cognitive performance at 18 y. Cox proportional-hazards models showed that cardiovascular fitness at age 18 y predicted educational achievements later in life. These data substantiate that physical exercise could be an important instrument for public health initiatives to optimize educational achievements, cognitive performance, as well as disease prevention at the society level.

Apoptosis-inducing factor is a major contributor to neuronal loss induced by neonatal cerebral hypoxia-ischemia

Nine-day-old harlequin (Hq) mice carrying the hypomorphic apoptosis-inducing factor (AIF)Hq mutation expressed 60% less AIF, 18% less respiratory chain complex I and 30% less catalase than their wild-type (Wt) littermates. Compared with Wt, the infarct volume after hypoxia-ischemia (HI) was reduced by 53 and 43% in male (YXHq) and female (XHqXHq) mice, respectively (P<0.001). The Hq mutation did not inhibit HI-induced mitochondrial release of cytochrome c or activation of calpain and caspase-3. The broad-spectrum caspase inhibitor quinoline-Val-Asp(OMe)-CH2-PH (Q-VD-OPh) decreased the activation of all detectable caspases after HI, both in Wt and Hq mice. Q-VD-OPh reduced the infarct volume equally in Hq and in Wt mice, and the combination of Hq mutation and Q-VD-OPh treatment showed an additive neuroprotective effect. Oxidative stress leading to nitrosylation and lipid peroxidation was more pronounced in ischemic brain areas from Hq than Wt mice. The antioxidant edaravone decreased oxidative stress in damaged brains, more pronounced in the Hq mice, and further reduced brain injury in Hq but not in Wt mice. Thus, two distinct strategies can enhance the neuroprotection conferred by the Hq mutation, antioxidants, presumably compensating for a defect in AIF-dependent redox detoxification, and caspase inhibitors, presumably interrupting a parallel pathway leading to cellular demise.

Astrocytes and stroke: Networking for survival?

Astrocytes are now known to be involved in the most integrated functions of the central nervous system. These functions are not only necessary for the normally working brain but are also critically involved in many pathological conditions, including stroke. Astrocytes may contribute to damage by propagating spreading depression or by sending proapoptotic signals to otherwise healthy tissue via gap junction channels. Astrocytes may also inhibit regeneration by participating in formation of the glial scar. On the other hand, astrocytes are important in neuronal antioxidant defense and secrete growth factors, which probably provide neuroprotection in the acute phase, as well as promoting neurogenesis and regeneration in the chronic phase after injury. A detailed understanding of the astrocytic response, as well as the timing and location of the changes, is necessary to develop effective treatment strategies for stroke patients.

Astroglia and glutamate in physiology and pathology: aspects on glutamate transport, glutamate-induced cell swelling and gap-junction communication

Astroglia have the capacity to monitor extracellular glutamate (Glu) and maintain it at low levels, metabolize Glu, or release it back into the extracellular space. Glu can induce an increase in astroglial cell volume with a resulting decrease of the extracellular space, and thereby alter the concentration of extracellular substances. Many lines of evidence show that K(+) can be buffered within the astroglial gap-junction-coupled network, and recent results show that gap junctions are permeable for Glu. All these events occur dynamically: the astroglial network has the capacity to interfere actively with neurotransmission, thereby contributing to a high signal-to-noise ratio for the Glu transmission. High-quality neuronal messages during normal physiology can then be maintained. With the same mechanisms, astroglia might exert a neuroprotective function in situations of moderately increased extracellular Glu concentrations, i.e., corresponding to conditions of pathological hyper-excitability, or corresponding to early stages of an acute brain injury. If the astroglial functions are failing, neuronal dysfunction can be reinforced.

Acute and Chronic Stress-Induced Disturbances of Microglial Plasticity, Phenotype and Function

Traditionally, microglia have been considered to act as macrophages of the central nervous system. While this concept still remains true it is also becoming increasingly apparent that microglia are involved in a host of non-immunological activities, such as monitoring synaptic function and maintaining synaptic integrity. It has also become apparent that microglia are exquisitely sensitive to perturbation by environmental challenges. The aim of the current review is to critically examine the now substantial literature that has developed around the ability of acute, sub-chronic and chronic stressors to alter microglial structure and function. The vast majority of studies have demonstrated that stress promotes significant structural remodelling of microglia, and can enhance the release of pro-inflammatory cytokines from microglia. Mechanistically, many of these effects appear to be driven by traditional stress-linked signalling molecules, namely corticosterone and norepinephrine. The specific effects of these signalling molecules are, however, complex as they can exert both inhibitory and suppressive effects on microglia depending upon the duration and intensity of exposure. Importantly, research has now shown that these stress-induced microglial alterations, rather than being epiphenomena, have broader behavioural implications, with the available evidence implicating microglia in directly regulating certain aspects of cognitive function and emotional regulation.

Modulation of Neural Plasticity as a Basis for Stroke Rehabilitation

Current understanding of the mechanisms underlying neural plasticity changes after stroke stems from experimental models as well as clinical studies and provides the foundation for evidence-based neurorehabilitation. In this review, we first describe the main structural and functional constituents of neural plasticity that are believed to contribute to recovery of function after stroke. Next, we discuss selected behavioral manipulations and adjuvant therapies that can stimulate neural plasticity and improve recovery of function, particularly when applied in combination with task-specific physiotherapy and in a stimulating environment. ### Experience-Dependent Plasticity of the Cerebral Cortex Cerebral cortex is an assembly of neuronal cells that are highly interconnected. The morphology as well as function of these complex and spatially distributed networks are modulated or even controlled by the glial component of the central nervous system (CNS). The ability to adapt in response to the changing environment is the most fundamental property of the nervous tissue and constitutes the basis for learning. Neural plasticity is the neurobiological basis for the ability to adapt and learn in an experience-dependent manner.1 At the structural level, neural plasticity could be defined in terms of dendritic and axonal arborization, spine density, synapse number and size, receptor density, and in some brain regions also the number of neurons. These structural constituents of neural plasticity jointly determine the complexity of neuronal networks and their activity and contribute to recovery of function after stroke and other CNS injury. ### Spontaneous Recovery of Function After Stroke Loss of function attributable to stroke is caused by cell death in the infarcted region as well as cell dysfunction in the areas surrounding the infarct. In addition, the function of remote brain regions, including the contralateral areas that are connected to the area of tissue damage, is compromised because of hypometabolism, neurovascular uncoupling, and aberrant neurotransmission, jointly called diaschisis.1 Some recovery of function occurs spontaneously after stroke in …