Intraventricular Infusion Research Articles

Co-morbid beta-amyloid toxicity and stroke produce impairments in an ambiguous context task in rats without any impairment in spatial working memory

Sporadic Alzheimer’s disease (AD) accounts for a high proportion of AD cases. Therefore, it is of importance to investigate other factors that contribute to the etiology and progression of AD. AD is characterized by decreased cholinergic tone, tau hyperphosphorylation and beta-amyloid (Aβ) accumulation. In addition to the hallmark pathology, other factors have been identified that increase the risk of AD, including stroke. This study examined the combined effects of beta-amyloid administration and unilateral stroke in an animal model of AD. Adult rats were given a sham surgery, bilateral intraventricular infusion of 10μL of 50nmol Aβ25–35, a unilateral injection of endothelin-1 into the right striatum, or Aβ and endothelin-1 administration in combination. Following a recovery period, rats were tested in the 1-trial place learning variant of the Morris water task followed by an ambiguous discriminative fear-conditioning to context task. After behavioural assessment, rats were euthanized, and representative sections of the medial septum were analyzed for differences in choline-acetyltransferase (ChAT) immunohistochemistry. No differences were observed in spatial working memory, but the combined effect of Aβ and stroke resulted in deficits in the discriminative fear-conditioning to context task. A trend towards decreased ChAT-positive staining in the medial septum was observed. This study indicates that Aβ and stroke in combination produce worse functional consequences than when experienced alone, furthering the concept of AD as a disease with multiple and complex etiologies.

Effects of pigment epithelium-derived factor on traumatic brain injury.

Pigment epithelium-derived factor (PEDF) is a multifunctional protein with antiangiogenic, anti-inflammatory, neurotrophic and neurogenic properties. The effect of PEDF on traumatic brain injury (TBI) has not been explored. In this study, we aimed to show the in vivo effects of PEDF on lesion volume, cell death and cell proliferation after TBI. Rats were subjected to controlled cortical impact injury (CCII). PEDF mRNA brain levels were measured by RT-PCR. The lesion volume, cell proliferation, cell death and microglia activation were assessed in the brains of lesioned animals with intraventricular alzet infusion of PEDF or aCSF, and intraperitoneal injections of BrdU. We detected a significant increase of PEDF mRNA levels after TBI. PEDF intraventricular infusion showed no significant effect on the contusion volume, whereas the number of dead cells, activated microglia, BrdU-positive cells around the lesion were significantly decreased. In contrast, PEDF application increased cell proliferation in the ipsilateral subventricular zone. No effect was found on cell proliferation in the dentate gyrus. The present work indicates that PEDF acts as a multifunctional agent after TBI influencing cell death, inflammation and cell proliferation.

Acupuncture: a potent therapeutic tool for inducing adult neurogenesis.

Acupuncture has been broadly used as a major therapeutic tool for at least 2,100 years in East Asia. Acupuncture is used for improving the pathological condition of remote organs, such as stomach, liver, brain, etc. by stimulating skin and muscle with fine metal needles through meridians which have been regarded as pathways of Qi within the body (Ernst, 2006). Physicians in East Asia have tried to treat many kinds of diseases by acupuncture and it was considerably successful. Various diseases for which acupuncture is known to be effective, are neurological diseases, including sequelae of stroke, Alzheimer's disease (AD), Parkinson's disease (PD), and so on (Nam et al., 2013).

A novel method to study cerebrospinal fluid dynamics in rats

Cerebrospinal fluid (CSF) flow dynamics play critical roles in both the immature and adult brain, with implications for neurodevelopment and disease processes such as hydrocephalus and neurodegeneration. Remarkably, the only reported method to date for measuring CSF formation in laboratory rats is the indirect tracer dilution method (a.k.a., ventriculocisternal perfusion), which has limitations. Anesthetized rats were mounted in a stereotaxic apparatus, both lateral ventricles were cannulated, and the Sylvian aqueduct was occluded. Fluid exited one ventricle at a rate equal to the rate of CSF formation plus the rate of infusion (if any) into the contralateral ventricle. Pharmacological agents infused at a constant known rate into the contralateral ventricle were tested for their effect on CSF formation in real-time. The measured rate of CSF formation was increased by blockade of the Sylvian aqueduct but was not changed by increasing the outflow pressure (0-3cm of H2O). In male Wistar rats, CSF formation was age-dependent: 0.39±0.06, 0.74±0.05, 1.02±0.04 and 1.40±0.06μL/min at 8, 9, 10 and 12 weeks, respectively. CSF formation was reduced 57% by intraventricular infusion of the carbonic anhydrase inhibitor, acetazolamide. Tracer dilution methods do not permit ongoing real-time determination of the rate of CSF formation, are not readily amenable to pharmacological manipulations, and require critical assumptions. Direct measurement of CSF formation overcomes these limitations. Direct measurement of CSF formation in rats is feasible. Our method should prove useful for studying CSF dynamics in normal physiology and disease models.

Interim Results of a Phase I Study of Lenalidomide (CC-5013) Plus Intraventricular/Intravenous Rituximab for Recurrent/Refractory CNS and Intraocular Lymphoma

BACKGROUND: There is an unmet need for effective therapies for relapsed/refractory primary and secondary central nervous system (CNS) and intraocular lymphomas (IOL), complications that are increasing in frequency among patients age >60. Whole brain irradiation, broadly utilized in the relapsed setting, yields insufficient efficacy and considerable morbidity, particularly in older patients. Implementation of new agents that selectively target survival pathways upregulated in refractory CNS lymphoma would have significant impact. Lenalidomide (CC-5013) has established activity as a single agent in aggressive NHL, particularly in ABC-type DLBCL. We recently demonstrated the activity of lenalidomide, at modest doses, in the treatment of recurrent/refractory intraocular and CNS lymphoma (J. Clin Oncol, 2011). We also provided evidence of cereblon-dependent efficacy of lenalidomide in preclinical models of patient-derived CNS DLBCL (ASH, 2013). These observations are the basis for this first trial of IMiD® immunomodulatory compound therapy in CNS NHL, as monotherapy, and in patients with inadequate responses to lenalidomide, in combination with combined intravenous plus intraventricular rituximab. (NCT01542918).METHODS: The primary objective of this phase I study is to evaluate the safety and efficacy of lenalidomide at three dose levels (10, 20, and 30mg) in relapsed/refractory CD20+ CNS NHL, with staging evaluations involving brain, CSF and intraocular compartments. Key secondary endpoints include: (1) determination of extent of CSF penetration by lenalidomide; (2) feasibility and activity of combined intraventricular and intravenous rituximab plus lenalidomide in patients with recurrent CNS lymphoma, not responsive to lenalidomide monotherapy; (3) evaluation of the effects of lenalidomide on the tumor microenvironment, including effects on tumor metabolism and immune cell infiltration and phenotypes.RESULTS: Thus far, seven subjects with relapsed CNS DLBCL (6 PCNSL, 1 SCNSL) have been treated on protocol at UCSF (median age 63, range 46-77). Each had methotrexate-resistant disease and 4 had lymphoma refractory to high-dose chemotherapy. In general, lenalidomide has been well-tolerated in the CNS lymphoma population with one DLT (non-hematologic) noted at the 20 mg dose level: fatigue and memory loss. Clinical benefit has been noted in 3 out of 4 patients with IOL, with 1 PR > 6 months duration and 1 SD > 10 months duration, each to lenalidomide monotherapy. Brain parenchymal responses to lenalidomide monotherapy (20 mg) have been demonstrated at restaging MRI, including 1 CR and 1 PR. There has been 1 CR in the leptomeninges with resolution of B-cell lymphoma in CSF, quantified by serial flow-cytometry. Combined intraventricular (20 mg) plus intravenous infusion of rituximab was well-tolerated in 3/3 patients and, with 10 mg lenalidomide, resulted in 1 PR in highly refractory IOL. Using GC/MS, we demonstrated lenalidomide penetration in ventricular CSF (0.6-7.9 ng/ml) in each of 4 patients, 12-15 hours after dosing at the 20 mg level, but trough lenalidomide concentrations >0.5 ng/ml were detected in only 1 of 3 patients receiving 10 mg lenalidomide. Serial metabolomic profiling revealed that CSF lactate correlated with clinical response to lenalidomide. Finally, we demonstrated that lenalidomide is reproducibly associated with a rapid and reversible effect on peripheral blood macrophage polarization to an M1, iNOS+ phenotype.CONCLUSIONS: These preliminary results provide evidence that lenalidomide is well-tolerated at 10 and 20 mg dose levels in CNS lymphoma. We demonstrate for the first time lenalidomide penetration in ventricular CSF, with higher trough concentrations detected at 20 mg compared to the 10 mg dose level. Encouraging evidence of lenalidomide efficacy in relapsed CNS DLBCL has been demonstrated in intraocular, CSF and brain compartments. Combined intraventricular and intravenous infusion of rituximab is feasible and represents a novel strategy to the potentiation of immunotherapeutic strategies in brain tumors. Studies are in progress to further elucidate the safety, pharmacokinetics and mechanisms involved in this biological approach to the treatment of refractory CNS lymphomas.Supported by NCI, Leukemia and Lymphoma Society, UCSF Helen Diller Comprehensive Cancer Center, Celgene and Genentech DisclosuresOff Label Use: Intrathecal administration of rituximab. Wang:Celgene: Employment. Chen:Celgene: Employment.

Neurogenesis is enhanced by stroke in multiple new stem cell niches along the ventricular system at sites of high BBB permeability

Previous studies have established the subventricular (SVZ) and subgranular (SGZ) zones as sites of neurogenesis in the adult forebrain (Doetsch et al., 1999a; Doetsch, 2003a). Work from our laboratory further indicated that midline structures known as circumventricular organs (CVOs) also serve as adult neural stem cell (NSC) niches (Bennett et al., 2009, 2010). In the quiescent rat brain, NSC proliferation remains low in all of these sites. Therefore, we recently examined whether ischemic stroke injury (MCAO) or sustained intraventricular infusion of the mitogen bFGF could trigger an up-regulation in NSC proliferation, inducing neurogenesis and gliogenesis. Our data show that both stroke and bFGF induce a dramatic and long-lasting (14day) rise in the proliferation (BrdU+) of nestin+Sox2+GFAP+ NSCs capable of differentiating into Olig2+ glial progenitors, GFAP+nestin-astrocyte progenitors and Dcx+ neurons in the SVZ and CVOs. Moreover, because of the upsurge in NSC number, it was possible to detect for the first time several novel stem cell niches along the third (3V) and fourth (4V) ventricles. Importantly, a common feature of all brain niches was a rich vasculature with a blood–brain-barrier (BBB) that was highly permeable to systemically injected sodium fluorescein. These data indicate that stem cell niches are more extensive than once believed and exist at multiple sites along the entire ventricular system, consistent with the potential for widespread neurogenesis and gliogenesis in the adult brain, particularly after injury. We further suggest that because of their leaky BBB, stem cell niches are well-positioned to respond to systemic injury-related cues which may be important for stem-cell mediated brain repair.

Influence of pigment epithelium-derived factor on outcome after striatal cerebral ischemia in the mouse.

We here suggest that pigment epithelium-derived factor (PEDF) does not have an effect on lesion size, behavioral outcome, cell proliferation, or cell death after striatal ischemia in the mouse. PEDF is a neurotrophic factor with neuroprotective, antiangiogenic, and antipermeability effects. It influences self-renewal of neural stem cells and proliferation of microglia. We investigated whether intraventricular infusion of PEDF reduces infarct size and cell death, ameliorates behavioral outcome, and influences cell proliferation in the one-hour middle cerebral artery occlusion (MCAO) mouse model of focal cerebral ischemia. C57Bl6/N mice were implanted with PEDF or artificial cerebrospinal fluid (control) osmotic pumps and subjected to 60-minute MCAO 48 hours after pump implantation. They received daily BrdU injections for 7 days after MCAO in order to investigate cell proliferation. Infarct volumes were determined 24 hours after reperfusion using magnetic resonance imaging. We removed the pumps on day 5 and performed behavioral testing between day 7 and 21. Immunohistochemical staining was performed to determine the effect of PEDF on cell proliferation and cell death. Our model produced an ischemic injury confined solely to striatal damage. We detected no reduction in infarct sizes and cell death in PEDF- vs. CSF-infused MCAO mice. Behavioral outcome and cell proliferation did not differ between the groups. However, we cannot exclude that PEDF might work under different conditions in stroke. Further studies will elucidate the effect of PEDF treatment on cell proliferation and behavioral outcome in moderate to severe ischemic injury in the brain.

Another chapter in the understanding of angiotensin-catecholamine interactions relevant to blood pressure control.

Another chapter in the understanding of angiotensin-catecholamine interactions relevant to blood pressure control.

Improvement of biochemical and behavioral defects in the Niemann–Pick type A mouse by intraventricular infusion of MARCKS

Niemann–Pick disease type A (NPDA) is a fatal disease due to mutations in the acid sphingomyelinase (ASM) gene, which triggers the abnormal accumulation of sphingomyelin (SM) in lysosomes and the plasma membrane of mutant cells. Although the disease affects multiple organs, the impact on the brain is the most invalidating feature. The mechanisms responsible for the cognitive deficit characteristic of this condition are only partially understood. Using mice lacking the ASM gene (ASMko), a model system in NPDA research, we report here that high sphingomyelin levels in mutant neurons lead to low synaptic levels of phosphoinositide PI(4,5)P2 and reduced activity of its hydrolyzing phosphatase PLCγ, which are key players in synaptic plasticity events. In addition, mutant neurons have reduced levels of membrane-bound MARCKS, a protein required for PI(4,5)P2 membrane clustering and hydrolysis. Intracerebroventricular infusion of a peptide that mimics the effector domain of MARCKS increases the content of PI(4,5)P2 in the synaptic membrane and ameliorates behavioral abnormalities in ASMko mice.

The effect of stromal cell-derived factor 1 in the migration of neural stem cells.

Neural stem cells (NSCs) have widely been used in the treatment of human neurological disorders as cell therapy via intracerebral or intraventricular infusion. However, the migration mechanism required for NSCs homing and recruitment remains to be elucidated. Recently, SDF-1/CXCR4 axis was shown to be responsible for in cell migration and differentiation during the neural development stage and involved in the pathophysiological process of neurological disorders. In this study, we investigated the effect of SDF-1 in migration of NSCs in vitro and in vivo. The expression of CXCR4 receptor was examined by immunocytochemistry and RT-PCR. The migratory ability of NSCs induced by SDF-1 was assessed by transwell chemotaxis assay. The traumatic brain injury rat model was well established, and the recruitment of NSCs and expression of SDF-1 were investigated in vivo. Our findings demonstrated that SDF-1, in vitro, significantly induced the migratory of NSCs in a dose-dependent manner. An overexpression of neural stem cell marker Nestin in the hippocampus was observed after TBI, and the expressions of SDF-1 surrounding the lesion areas were significantly increased. Our results suggested that the migration of NSCs was activated by chemotactic effect of SDF-1. It was also proved the relevance of SDF-1 in the migration of endogenous NSCs after brain injury. Taken together, these results demonstrated that SDF-1/CXCR4 axis may play crucial role in the migration of Nestin-positive cell after brain injury.

129. Blockade of L-type voltage dependent calcium channels or ryanodine receptors during chronic neuroinflammation improves spatial memory and reduces expression of inflammatory markers

Chronic neuroinflammation is a key component of Alzheimer’s disease and other neurodegenerative processes. Prolonged neuroinflammation produces elevation of pro-inflammatory cytokines as well as memory deficits. We have previously shown that neuroinflammation constitutively increases calcium-dependent immediate early gene expression which may underlie neuroinflammation-induced memory deficits. Enhancement of L-type voltage-dependent calcium channel (L-VDCC) and/or ryanodine receptor (RyR) activity may be related to neuroinflammation and lead to dysregulated increases of intracellular calcium and contribute to cognitive deficits. In order to examine the contribution of these two calcium channels to neuroinflammation-induced memory deficits, we pharmacologically targeted the L- VDCCs with nimodipine or the RyRs with dantrolene. To induce neuroinflammation, rats were treated with intraventricular infusion of lipopolysaccharide (LPS) for 28 days. We found that LPS-infused rats had significant memory deficits in the Morris water maze; this deficit was ameliorated by treatment with either nimodipine or dantrolene. We found significant increases in several inflammatory genes and microglia activation in the hippocampus of LPS-infused rats, both of which were reduced by treatment with either nimodipine or dantrolene, suggesting an anti-inflammatory effect of our pharmacological manipulations. Immediate early gene expression was also reduced to control levels in LPS-infused rats treated with dantrolene or nimodipine, indicating normalized synaptic function. Overall, these data suggest that calcium dysregulation via L-VDCCs and RyRs plays a crucial role in neuroinflammation-induced memory deficits.

Estrogen receptors regulate the estrous behavior induced by progestins, peptides, and prostaglandin E2

The role of classical estrogen receptors (ERs) in priming female reproductive behavior has been studied previously; however, the participation of this receptor during activation of estrous behavior has not been extensively studied. The purpose of this work was to test the possibility that the facilitation of lordosis behavior in estrogen-primed rats by progesterone (P) and its 5α- and 5β-reduced metabolites, gonadotropin-releasing hormone (GnRH), leptin, prostaglandin E2 (PGE2) and vagino-cervical stimulation (VCS) involves interactions with classical ERs by using the selective ER modulator, tamoxifen. To further assess the role of ERs, we also explored the effects of the pure ER antagonist, ICI182780 (ICI), on estrous behavior induced by P and GnRH. Ovariectomized, estrogen-primed rats (5μg estradiol benzoate 40h earlier) were injected intraventricularly with the above-mentioned compounds, or they received VCS. All compounds and VCS effectively facilitated estrous behavior when tested at 60, 120 or 240min after infusion or application of VCS. Intraventricular infusion of tamoxifen (5μg), 30min before, significantly attenuated estrous behaviors induced in estradiol-primed rats by P, most of its 5α- and 5β-reduced metabolites, GnRH, and PGE2, but not by VCS. Although there was a trend for reduction, tamoxifen did not significantly decrease lordosis in females treated with 5β-pregnan-3,20-dione. ICI also inhibited lordosis behavior induced by P and GnRH at some testing intervals. These results suggest that activation of classical ERs participates in the triggering effects on estrous behavior induced by agents with different chemical structures that do not bind directly to ERs.

Axonal Control of the Adult Neural Stem Cell Niche

The ventricular-subventricular zone (V-SVZ) is an extensive germinal niche containing neural stem cells (NSCs) in the walls of the lateral ventricles of the adult brain. How the adult brain's neural activity influences the behavior of adult NSCs remains largely unknown. We show that serotonergic (5HT) axons originating from a small group of neurons in the raphe form an extensive plexus on most of the ventricular walls. Electron microscopy revealed intimate contacts between 5HT axons and NSCs (B1) or ependymal cells (E1) and these cells were labeled by a transsynaptic viral tracer injected into the raphe. B1 cells express the 5HT receptors 2C and 5A. Electrophysiology showed that activation of these receptors in B1 cells induced small inward currents. Intraventricular infusion of 5HT2C agonist or antagonist increased or decreased V-SVZ proliferation, respectively. These results indicate that supraependymal 5HT axons directly interact with NSCs to regulate neurogenesis via 5HT2C.

GSK3β regulates oligodendrogenesis in the dorsal microdomain of the subventricular zone via Wnt-β-catenin signaling

Oligodendrocytes, the myelinating cells of the CNS, are derived postnatally from oligodendrocyte precursors (OPs) of the subventricular zone (SVZ). However, the mechanisms that regulate their generation from SVZ neural stem cells (NSC) are poorly understood. Here, we have examined the role of glycogen synthase kinase 3β (GSK3β), an effector of multiple converging signaling pathways in postnatal mice. The expression of GSK3β by rt-qPCR was most prominent in the SVZ and in the developing white matter, around the first 1–2 weeks of postnatal life, coinciding with the peak periods of OP differentiation. Intraventricular infusion of the GSK3β inhibitor ARA-014418 in mice aged postnatal day (P) 8–11 significantly increased generation of OPs in the dorsal microdomain of the SVZ, as shown by expression of cell specific markers using rt-qPCR and immunolabelling. Analysis of stage specific markers revealed that the augmentation of OPs occurred via increased specification from earlier SVZ cell types. These effects of GSK3β inhibition on the dorsal SVZ were largely attributable to stimulation of the canonical Wnt/β-catenin signaling pathway over other pathways. The results indicate GSK3β is a key endogenous factor for specifically regulating oligodendrogenesis from the dorsal SVZ microdomain under the control of Wnt-signaling.

Functional Connectivity Changes during Consolidation of Inhibitory Avoidance Memory in Rats: A Manganese-Enhanced MRI Study

Consolidation of memory involves transfer of encoded information into a durable neural representation, but how this is transacted in the nervous system remains elusive. It has been proposed that memory consolidation is subserved by formation of a cell assembly due to coincidence of pre- and post-synaptic activity therein after learning. To capture such off-line changes, manganese-enhanced magnetic resonance imaging (MEMRI) was used to trace brain activity during the memory consolidation period. Male Wistar rats were trained on the one-trial inhibitory avoidance task and received intraventricular infusion of manganese ion shortly after training. The MEMRI taken 1 day later showed that brain areas including the prelimbic, insular and anterior pirifrom cortices of the learning group had significantly lower memory-related MEMRI signal than those of the control group. The functional network was revealed by correlating the MEMRI signals among regions followed by graph theoretical analysis. Learning sculpted the non-discriminative connectivity among many brain regions in the controls into a network in the trained rats with selected connectivity among regions implicated in inhibitory avoidance learning. The network could be organized into three clusters presumably subserving different functions. The results suggest that the brain prunes excessive functional connectivity in a cell assembly to consolidate new memory.

Decorin prevents the development of juvenile communicating hydrocephalus

In post-haemorrhagic and other forms of communicating hydrocephalus, cerebrospinal fluid flow and drainage is obstructed by subarachnoid fibrosis in which the potent fibrogenic cytokine transforming growth factor-β has been aetiologically implicated. Here, the hypothesis that the transforming growth factor-β antagonist decorin has therapeutic potential for reducing fibrosis and ventriculomegaly was tested using a rat model of juvenile communicating hydrocephalus. Hydrocephalus was induced by a single basal cistern injection of kaolin in 3-week-old rats, immediately followed by 3 or 14 days of continuous intraventricular infusion of either human recombinant decorin or phosphate-buffered saline (vehicle). Ventricular expansion was measured by magnetic resonance imaging at Day 14. Fibrosis, transforming growth factor-β/Smad2/3 activation and hydrocephalic brain pathology were evaluated at Day 14 and the inflammatory response at Days 3 and 14 by immunohistochemistry and basic histology. Analysis of ventricular size demonstrated the development of hydrocephalus in kaolin-injected rats but also revealed that continuous decorin infusion prevented ventricular enlargement, such that ventricle size remained similar to that in intact control rats. Decorin prevented the increase in transforming growth factor-β1 and phosphorylated Smad2/3 levels throughout the ventricular system after kaolin injection and also inhibited the deposition of the extracellular matrix molecules, laminin and fibronectin in the subarachnoid space. In addition, decorin protected against hydrocephalic brain damage inferred from attenuation of glial and inflammatory reactions. Thus, we conclude that decorin prevented the development of hydrocephalus in juvenile rats by blocking transforming growth factor-β-induced subarachnoid fibrosis and protected against hydrocephalic brain damage. The results suggest that decorin is a potential clinical therapeutic for the treatment of juvenile post-haemorrhagic communicating hydrocephalus.

VPAC receptor signaling modulates grouping behavior and social responses to contextual novelty in a gregarious finch: A role for a putative prefrontal cortex homologue

In both mammals and birds, vasoactive intestinal polypeptide (VIP) neurons and fibers are present in virtually every brain area that is important for social behavior. VIP influences aggression in birds, social recognition in rodents, and prolactin secretion in both taxa, but other possible functions in social modulation remain little explored. VIP effects are mediated by VPAC receptors, which bind both VIP and pituitary adenylate cyclase activating peptide. Within the lateral septum and medial bed nucleus of the stria terminalis, VPAC receptors are found at higher densities in gregarious finch species relative to territorial species, suggesting that VPAC receptor activation promotes social contact and/or preference for larger groups. Here we here test this hypothesis in zebra finches (Taeniopygia guttata), and also examine the relevance of VPAC receptors to anxiety-like processes. Intraventricular infusions of the VPAC receptor antagonist, neurotensin6–11 mouseVIP7–28, strongly reduce social contact when animals are tested in a novel environment, and exert sex-specific effects on grouping behavior. Specifically, VPAC receptor antagonism reduces gregariousness in females but increases gregariousness in males. Interestingly, VPAC antagonism in the medial pallium (putative prefrontal cortex homologue) significantly reduces gregariousness in both sexes, suggesting site-specific effects of VIP signaling. However, VPAC antagonism does not modulate novel-familiar social preferences in a familiar environment or general anxiety-like behaviors. The current results suggest that endogenous activation of VPAC receptors promotes social contact under novel environmental conditions, a function that may be accentuated in gregarious species. Moreover, endogenous VIP modulates gregariousness in both males and females.

Infusion of cannabidiol into infralimbic cortex facilitates fear extinction via CB1 receptors

Previous studies have implicated cannabinoids in extinction of conditioned fear. We have recently showed that intraventricular infusion of the phytocannabinoid cannabidiol (CBD) facilitates fear extinction, but the brain regions underlying this effect remained unknown. Here we demonstrate that repeated microinjections of CBD into the infralimbic cortex (IL) facilitated fear extinction, as indicated by reduced levels of freezing during extinction test. Systemic administration of the CB1 receptor antagonist rimonabant blocked the effects of intra-IL CBD, suggesting that CBD acts through CB1 receptors to facilitate fear extinction. Our findings suggest a potential therapeutic use of CBD for extinction-based therapies of aversive memories in humans.

MicroRNA-17-92 Cluster Mediates the Proliferation and Survival of Neural Progenitor Cells after Stroke

The role of microRNAs (miRNAs) in mediating adult neurogenesis after stroke has not been extensively studied. The present study investigated the function of the miR17-92 cluster in adult neural progenitor cells after experimental stroke. We found that stroke substantially up-regulated miR17-92 cluster expression in neural progenitor cells of the adult mouse. Overexpression of the miR17-92 cluster either in cultured ischemic neural progenitor cells or in the subventricular zone (SVZ) of ischemic animals significantly increased cell proliferation, whereas inhibition of individual members of the miR17-92 cluster, miR-18a and miR-19a, suppressed cell proliferation and increased cell death. The miR17-92 cluster mediated PTEN (phosphatase and tensin homolog) expression, which is a predicted target of the miR17-92 cluster. Addition of Sonic hedgehog (Shh) protein up-regulated miR17-92 expression and elevated c-Myc protein in ischemic neural progenitor cells, whereas blockade of the Shh signaling pathway down-regulated miR17-92 cluster expression and reduced c-Myc levels. Overexpression of c-Myc up-regulated miR17-92 cluster expression. Intraventricular infusion of Shh and a Shh receptor inhibitor, cyclopamine, to ischemic animals further elevated and suppressed, respectively, miR17-92 cluster expression in the SVZ. These data indicate that the miR17-92 cluster plays an important role in mediating neural progenitor cell function and that the Shh signaling pathway is involved in up-regulating miR17-92 cluster expression.

1H-MRS can monitor metabolites changes of lateral intraventricular BDNF infusion into a mouse model of Alzheimer’s disease in vivo

Proton magnetic resonance spectroscopy (1H-MRS) can provide noninvasive detection of brain metabolite changes in vivo in Alzheimer's disease (AD). AD is a prevalent neurodegenerative disorder characterized by deposition of β-amyloid peptides (Aβ) in multiple brain regions. Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor whose level has been shown to be decreased in AD. BDNF supplementation can offer improvement in AD. However, the means of evaluation are still relatively limited. In the present study, 1H-MRS was applied to evaluate the therapeutic effects of bilateral intraventricular BDNF infusion into APP+PS1 (amyloid precursor protein+presenilin 1) transgenic mice. For comparison to the 1H-MRS changes in the prefrontal cortex, Morris water maze (MWM) test, Fluoro-Jade B staining and immunofluorescence for Aβ, glial fibrillary acidic protein and tropomyosin-related kinase B (TrkB) were also performed. Our results showed that N-acetylaspartate (NAA) levels increased and myo-inositol levels decreased in Tg-BDNF mice compared with Tg-PBS mice. But NAA level in Tg-BDNF mice was still lower than that in wild-type mice at 6weeks after infusion. These changes correlated with increased immunoreactivity of TrkB, reduced compact Aβ peptide and FJB+ neurons in Tg-BDNF mice compared to Tg-PBS mice. However, Tg-BDNF mice did not present obvious changes in behavior in the MWM. Taken together, we suggest that 1H-MRS may be a sensitive means of evaluating metabolic changes in response to therapeutic strategies in AD. Moreover, BDNF, may be a viable means of offering trophic support during disease.