Striatal oligodendrogliogenesis and neuroblast recruitment are increased in the R6/2 mouse model of Huntington's disease

“Persistent neurogenesis occurs in the adult mammalian (including human) brain within the subventricular zone (SVZ) lining the lateral ventricles and in the subgranular zone of the hippocampus (Eriksson et al., 1998; Zhao et al., 2008).”

“This strain expresses exon 1 of the human huntingtin gene, containing ∼160 CAG repeats (Mangiarini et al., 1996).”

“Persistent neurogenesis occurs in the adult mammalian (including human) brain within the subventricular zone (SVZ) lining the lateral ventricles and in the subgranular zone of the hippocampus (Eriksson et al., 1998; Zhao et al., 2008).”

“The numbers of BrdU-immunopositive cells were counted in each grid of the Z-stack image following the optical dissector method as described by West et al. (1991).”

“…to playing a critical role in neuronal plasticity in the normal brain, there is an increasing evidence that adult neurogenesis is modulated by and responsive to brain injuries and diseases (Arvidsson et al., 2002; Curtis et al., 2007; Kernie and Parent, 2010; Ohira, 2011; Winner et al., 2011).”

“Under normal physiological conditions, the vast majority of neuroblasts generated in the SVZ migrate to the olfactory bulb in the rostral migratory stream (Ming and Song, 2005).”

“It has been reported that apoptotic newborn cells are rapidly cleared out through phagocytosis by unchallenged microglia present in the adult SGZ niche (Sierra et al., 2010) and apoptotic cells are phagocytosed within 1–2 h from the start of apoptosis in most tissues (Savill, 1997).”

“To test if increased endogenous BDNF could promote the recruitment and survival of new neurons in the degenerating striatum, we crossed the R6/2 strain with transgenic mice (BTg) that overexpress BDNF throughout the forebrain, including the cortex and striatum (Huang et al., 1999).”

“…strong evidence suggesting an important role for NG2-expressing cells in cellular homeostasis, such as responding to neuronally released glutamate (Bergles et al., 2000; Polito and Reynolds, 2005) Importantly, excessive glutamate release has been proposed as an important factor in the striatal…”

“Huntington's disease (HD) is a fatal inherited neurodegenerative disease caused by a mutation in the huntingtin gene and characterized by the progressive loss of striatal GABAergic medium spiny neurons (MSNs), which constitute 95% of striatal neurons (Reiner et al., 1988).”

“Reduced striatal BDNF has been shown in both HD patients (Ferrer et al., 2000) and transgenic models of HD (Zuccato and Cattaneo, 2009).”

“For example, infusion or adenoviral delivery of BDNF into ventricles induces SVZ proliferation and neurogenesis in the striatum of rodents (Benraiss et al., 2001; Pencea et al., 2001).”

“BDNF supplied by cortical afferents has been established as an important factor for the maintenance of striatal neurons in adults, and reduced levels of striatal BDNF have been demonstrated in both HD patients and animal models (Zuccato et al., 2010).”

“This raises the intriguing possibility that neurogenic regions may be manipulated to generate replacement neurons in damaged areas of the adult brain (Lie et al., 2004; Gil-Mohapel et al., 2011; Saha et al., 2012).”

“On the other hand, increased cell proliferation and neurogenesis were found in the subependymal layer of adult human HD brain using endogenous mitotic marker proliferating cell nuclear antigen (PCNA) (Curtis et al., 2003).”

“For example, infusion or adenoviral delivery of BDNF into ventricles induces SVZ proliferation and neurogenesis in the striatum of rodents (Benraiss et al., 2001; Pencea et al., 2001).”

“To test this possibility, we included a cellspecific marker for early post-mitotic neurons, calretinin (CR), in our studies (Brandt et al., 2003).”

“…to playing a critical role in neuronal plasticity in the normal brain, there is an increasing evidence that adult neurogenesis is modulated by and responsive to brain injuries and diseases (Arvidsson et al., 2002; Curtis et al., 2007; Kernie and Parent, 2010; Ohira, 2011; Winner et al., 2011).”

“In addition to its clinical potential, adult neurogenesis has also been implicated in the pathogenesis of HD and other neurodegenerative diseases (Phillips et al., 2005; Winner et al., 2011).”

“The behavioral benefits of elevated BDNF levels in the HD mouse models have been well studied (Canals et al., 2004; Gharami et al., 2008; Xie et al., 2010) and are not the focus of the current study.”

“Reduced striatal BDNF has been shown in both HD patients (Ferrer et al., 2000) and transgenic models of HD (Zuccato and Cattaneo, 2009).”

“It has been reported that apoptotic newborn cells are rapidly cleared out through phagocytosis by unchallenged microglia present in the adult SGZ niche (Sierra et al., 2010) and apoptotic cells are phagocytosed within 1–2 h from the start of apoptosis in most tissues (Savill, 1997).”

“Our data demonstrate that the numbers of BrdUpositive (BrdU+) cells are significantly increased in the striatum of R6/2 mice, and that the majority of these cells are oligodendrocytes and oligodendroglial progenitor cells (OPCs) arising within the striatum.”

“Structural magnetic resonance imaging and postmortem examinations in HD brains suggest that disruptions in white matter integrity resulting myelin breakdown represent an early event in HD pathogenesis (Bartzokis et al., 2007; Rosas et al., 2010; Xiang et al., 2011).”

“Interestingly, an increase in the density of oligodendrocytes in the striatum was demonstrated in presymptomatic HD patient brains years before striatal degeneration (Myers et al., 1991; Gómez-Tortosa et al., 2001).”

“Structural magnetic resonance imaging and postmortem examinations in HD brains suggest that disruptions in white matter integrity resulting myelin breakdown represent an early event in HD pathogenesis (Bartzokis et al., 2007; Rosas et al., 2010; Xiang et al., 2011).”

“The behavioral benefits of elevated BDNF levels in the HD mouse models have been well studied (Canals et al., 2004; Gharami et al., 2008; Xie et al., 2010) and are not the focus of the current study.”

“It has been reported that the mammalian adult brain responds rapidly to demyelinating insults by regenerating myelinating oligodendrocytes from dividing NG2+ cells (Polito and Reynolds, 2005).”

“The death of DCX+ cells in WT mice is not surprising since most immature neurons die before they can be functionally integrated into the circuitry in both SVZ and SGZ of adult normal animals (Sun et al., 2004; Sierra et al., 2010).”

“…can stimulate SVZ-derived neuroblasts to migrate instead into the adjacent striatum and mature into neurons in HD mouse models, with beneficial effects that manifest as a slowing of disease progression (Pencea et al., 2001; Chmielnicki et al., 2004; Cho et al., 2007; Gharami et al., 2008).”

“Our data demonstrate that the numbers of BrdUpositive (BrdU+) cells are significantly increased in the striatum of R6/2 mice, and that the majority of these cells are oligodendrocytes and oligodendroglial progenitor cells (OPCs) arising within the striatum.”

“In support of this hypothesis, it has been shown that NG2+ cells derived from the adult spinal cord express high levels of laminin and fibronectin and these proteins promote neurite outgrowth on the surface of these cells (Busch et al., 2010).”

“In contrast, SVZ proliferation has been reported as unchanged in several HD mouse models including R6/2 mice (Lazic et al., 2006; Kohl et al., 2010; Simpson et al., 2011).”

“Similar combinations of noggin and BDNF administration have been successfully used to induce new striatal neuron formation in rats (Chmielnicki et al., 2004; Benraiss et al., 2012).”

“In addition, morphological studies of the corticostriatal circuit in HD patients and animals have supported a “dying back” pattern of degeneration in HD (Han et al., 2010).”

“Reduced hippocampal neurogenesis has been reported in HD animals models and is potentially related to the cognitive abnormalities in HD (Lazic et al., 2004; Gil et al., 2005; Simpson et al., 2011).”

“However, no significant changes in SVZ neurogenesis have been found in these mouse models (Lazic et al., 2004; Phillips et al., 2005; Gil-Mohapel et al., 2011; Simpson et al., 2011).”

“…can stimulate SVZ-derived neuroblasts to migrate instead into the adjacent striatum and mature into neurons in HD mouse models, with beneficial effects that manifest as a slowing of disease progression (Pencea et al., 2001; Chmielnicki et al., 2004; Cho et al., 2007; Gharami et al., 2008).”

“Structural magnetic resonance imaging and postmortem examinations in HD brains suggest that disruptions in white matter integrity resulting myelin breakdown represent an early event in HD pathogenesis (Bartzokis et al., 2007; Rosas et al., 2010; Xiang et al., 2011).”

“…for NG2-expressing cells in cellular homeostasis, such as responding to neuronally released glutamate (Bergles et al., 2000; Polito and Reynolds, 2005) Importantly, excessive glutamate release has been proposed as an important factor in the striatal cell death observed HD (Paoletti et al., 2008).”

“In addition to its clinical potential, adult neurogenesis has also been implicated in the pathogenesis of HD and other neurodegenerative diseases (Phillips et al., 2005; Winner et al., 2011).”

“In adult primates, adenoviral BDNF injected into the lateral ventricles promotes SVZ proliferation and migration of neuroblasts to the striatum (Bédard et al., 2006).”

“Using the 5-bromo-2deoxyuridine (BrdU) labeling approach, it has been shown by most studies that hippocampal neurogenesis is reduced in commonly used transgenic HD mouse models, including R6/2 (Phillips et al., 2005), R6/1 (Lazic et al., 2004; 2006) and YAC128 mice (Simpson et al., 2011).”

“…to playing a critical role in neuronal plasticity in the normal brain, there is an increasing evidence that adult neurogenesis is modulated by and responsive to brain injuries and diseases (Arvidsson et al., 2002; Curtis et al., 2007; Kernie and Parent, 2010; Ohira, 2011; Winner et al., 2011).”

“However, it is more likely that striatal neuroblasts do not differentiate into neurons without considerable pharmacological intervention (Kohl et al., 2010; Luzzati et al., 2011).”

“…to playing a critical role in neuronal plasticity in the normal brain, there is an increasing evidence that adult neurogenesis is modulated by and responsive to brain injuries and diseases (Arvidsson et al., 2002; Curtis et al., 2007; Kernie and Parent, 2010; Ohira, 2011; Winner et al., 2011).”

“Therapeutic replacement of MSNs thus represents a potential strategy for treating HD (Benraiss and Goldman, 2011).”

“This raises the intriguing possibility that neurogenic regions may be manipulated to generate replacement neurons in damaged areas of the adult brain (Lie et al., 2004; Gil-Mohapel et al., 2011; Saha et al., 2012).”

“This raises the intriguing possibility that neurogenic regions may be manipulated to generate replacement neurons in damaged areas of the adult brain (Lie et al., 2004; Gil-Mohapel et al., 2011; Saha et al., 2012).”

“A substantial (approximately 10-fold) increase in the number of BrdU+ cells in the striatum of R6/2 mice at 30 days after BrdU administration was reported (Batista et al., 2006).”

“Similar combinations of noggin and BDNF administration have been successfully used to induce new striatal neuron formation in rats (Chmielnicki et al., 2004; Benraiss et al., 2012).”

“This apparent short lifespan for adult-born neuroblasts on the diseased striatum is consistent with the limited survival of SVZ-derived neuroblasts reported for another mouse model of progressive striatal degeneration (Luzzati et al., 2011).”

“Sections were stored at −20 1C in antigen preservation solution (1% polyvinyl pyrrolidone, and 50% ethylene glycol in PBS) prior to processing (Burke et al., 2009).”

“For instance, in Huntington’s disease, oligodendrocyte-lineage cells proliferated within the striatum [63] but not in the SVZ [63–66].”

“Over-expression of BDNF in the striatum of R6/2-BDNF mice appears to further enhance this recruitment, with more cells diverted (McCollum et al. 2013).”

“Under demyelinating conditions including pre-HD stage, it can induce proliferation of neural stem cells (NSCs) and neural progenitors [17], give rise to oligodendrocyte progenitor cells (OPCs) [18], and then differentiate into oligodendrocytes [11].”