New hippocampal neurons are continuously generated in the adult brain. Here, we demonstrate that lipopolysaccharide-induced inflammation, which gives rise to microglia activation in the area where the new neurons are born, strongly impairs basal hippocampal neurogenesis in rats. The increased neurogenesis triggered by a brain insult is also attenuated if it is associated with microglia activation caused by tissue damage or lipopolysaccharide infusion. The impaired neurogenesis in inflammation is restored by systemic administration of minocycline, which inhibits microglia activation. Our data raise the possibility that suppression of hippocampal neurogenesis by activated microglia contributes to cognitive dysfunction in aging, dementia, epilepsy, and other conditions leading to brain inflammation. In the adult mammalian brain, neural progenitor cells located in the subgranular zone (SGZ) of the dentate gyrus (DG) generate thousands of new neurons each day (1). These neurons develop the morphological and functional properties of dentate granule cells and become integrated into existing neuronal circuitries (2). The role of neurogenesis for hippocampal function is still unclear, but some experimental evidence suggests its involvement in memory formation (3) and mood regulation (4). Impairment of hippocampal neurogenesis may be linked to the cognitive decline in aging, Alzheimer's disease (AD), and major depression (5-7).Brain inflammation probably plays an important role in the pathogenesis of chronic neurodegenerative disorders like AD and ParkinsonЈs disease (8, 9). Neurodegeneration caused by inflammation involves activation of the brain's resident immune cells, the microglia, which produce a large number of proinflammatory factors (10-12). Also, acute brain insults, e.g., stroke and status epilepticus (SE), are linked to inflammation (13,14), which contributes to the propagation of the neuropathological events (9, 15). These insults trigger increased neurogenesis in the SGZ (16)(17)(18)(19). After severe SE, there is an 80% loss of newly formed dentate neurons (20), which raises the possibility that the associated inflammatory response is deleterious for hippocampal neurogenesis.Here, we show that the microglia activation associated with inflammation impairs both basal and insult-induced hippocampal neurogenesis. We find that systemic administration of the tetracycline derivative minocycline, which specifically inhibits microglia activation, is an effective treatment to restore neurogenesis suppressed by inflammation. Materials and MethodsSurgery and Induction of SE. Male Sprague-Dawley rats were implanted with a stimulating͞recording electrode into the right ventral hippocampus [coordinates: 4.8 mm caudal and 5.2 mm lateral to bregma, 6.3 mm ventral to dura, and toothbar at Ϫ3.3 mm (21)] under pentobarbital or halothane anesthesia. In 37 animals, a brain infusion cannula (Alzet, Palo Alto, CA) was also placed intracortically on the right side of the brain (2 mm caudal and 1.2 mm lateral to bregma and 2.6 mm ve...

Tumor necrosis factor-␣ (TNF-␣) is a proinflammatory cytokine, acting through the TNF-R1 and TNF-R2 receptors. The two receptors have been proposed to mediate distinct TNF-␣ effects in the CNS, TNF-R1 contributing to neuronal damage and TNF-R2 being neuroprotective. Whether TNF-␣ and its receptors play any role for neurogenesis in the adult brain is unclear. Here we used mouse models with loss of TNF-R1 and TNF-R2 function to establish whether signaling through these receptors could influence hippocampal neurogenesis in vivo under basal conditions, as well as after status epilepticus (SE), which is associated with inflammation and elevated TNF-␣ levels. Notably, in the intact brain, the number of new, mature hippocampal neurons was elevated in TNF-R1Ϫ/Ϫ and TNF-R1/R2 Ϫ/Ϫ mice, whereas no significant changes were detected in TNF-R2 Ϫ/Ϫ mice. Also after SE, the TNF-R1 Ϫ/Ϫ and TNF-R1/R2 Ϫ/Ϫ mice produced more new neurons. In contrast, the TNF-R2 Ϫ/Ϫ mice showed reduced SE-induced neurogenesis. Cell proliferation in the dentate subgranular zone was elevated in TNF-R1 Ϫ/Ϫ and TNF-R1/R2 Ϫ/Ϫ mice both under basal conditions and after SE. The TNF-R2 Ϫ/Ϫ mice either showed no change or minor decrease of cell proliferation. TNF-R1 and TNF-R2 receptors were expressed by hippocampal progenitors, as assessed with reverse transcription-PCR on sorted or cultured cells and immunocytochemistry on cultures. Our data reveal differential actions of TNF-R1 and TNF-R2 signaling in adult hippocampal neurogenesis and identify for the first time TNF-R1 as a negative regulator of neural progenitor proliferation in both the intact and pathological brain.

Neural progenitors in the adult dentate gyrus continuously produce new functional granule cells. Here we used whole-cell patch-clamp recordings to explore whether a pathological environment influences synaptic properties of new granule cells labeled with a GFP-retroviral vector. Rats were exposed to a physiological stimulus, i.e., running, or a brain insult, i.e., status epilepticus, which gave rise to neuronal death, inflammation, and chronic seizures. Granule cells formed after these stimuli exhibited similar intrinsic membrane properties. However, the new neurons born into the pathological environment differed with respect to synaptic drive and short-term plasticity of both excitatory and inhibitory afferents. The new granule cells formed in the epileptic brain exhibited functional connectivity consistent with reduced excitability. We demonstrate a high degree of plasticity in synaptic inputs to adult-born new neurons, which could act to mitigate pathological brain function.

The perspectives offered by vertical arrays of nanowires for biosensing applications in living cells depend on the access of individual nanowires to the cell interior. Recent results on electrical access and molecular delivery suggest that direct access is not always obtained. Here, we present a generic approach to directly visualize the membrane conformation of living cells interfaced with nanowire arrays, with single nanowire resolution. The method combines confocal z-stack imaging with an optimized cell membrane labelling strategy which was applied to HEK293 cells interfaced with 2-11 μm long and 3-7 μm spaced nanowires with various surface coatings (bare, aminosilane-coated or polyethyleneimine-coated indium arsenide). We demonstrate that, for all commonly used nanowire lengths, spacings and surface coatings, nanowires generally remain enclosed in a membrane compartment, and are thereby not in direct contact with the cell interior.