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PubMed1985

Stimulatory or inhibitory effects of angiotensin II upon LH secretion in ovariectomized rats: a function of gonadal steroids.

The effects of intraventricular infusions of artificial cerebrospinal fluid (aCSF) or angiotensin II (AII) on LH secretion were investigated in rats that had been ovariectomized for 8 days. In untreated ovariectomized rats, the mean whole blood concentration of LH as well as the amplitude, frequency, and nadir of the LH pulses were not affected by infusion of aCSF or 15 ng AII/h, but were suppressed in a dose-dependent fashion by infusion of AII at doses of 150 or 600 ng/h. The AII receptor antagonist, saralasin, blocked the inhibitory effect of AII, demonstrating the specificity of the response to AII. In ovariectomized rats pretreated with estradiol, infusion of AII did not modify mean blood LH levels. However, in ovariectomized rats pretreated with both estradiol and progesterone, infusions of AII at 150 or 600 ng/h produced dose-dependent increases in mean LH concentrations. The results demonstrate both inhibitory and stimulatory effects of AII upon LH secretion, the direction of the effect being determined by gonadal steroids.

Angiotensin II↗

PubMed2005

15d-prostaglandin J2 protects brain from ischemia-reperfusion injury.

OBJECTIVE: Brain expresses abundant lipocalin-type prostaglandin (PG) D2 (PGD2) synthase but the role of PGD2 and its metabolite, 15-deoxy-Delta(12,14) PGJ2 (15d-PGJ2) in brain protection is unclear. The aim of this study is to assess the effect of 15d-PGJ2 on neuroprotection. METHODS AND RESULTS: Adenoviral transfer of cyclooxygenase-1 (Adv-COX-1) was used to amplify the production of 15d-PGJ2 in ischemic cortex in a rat focal infarction model. Cortical 15d-PGJ2 in Adv-COX-1-treated rats was increased by 3-fold over control, which was correlated with reduced infarct volume and activated caspase 3, and increased peroxisome proliferator activated receptor-gamma (PPARgamma) and heme oxygenase-1 (HO-1). Intraventricular infusion of 15d-PGJ2 resulted in reduction of infarct volume, which was abrogated by a PPARgamma inhibitor. Rosiglitazone infusion had a similar effect. 15d-PGJ2 and rosiglitazone at low concentrations suppressed H2O2-induced rat or human neuronal apoptosis and necrosis and induced PPARgamma and HO-1 expression. The anti-apoptotic effect was abrogated by PPARgamma inhibition. CONCLUSIONS: 15d-PGJ2 suppressed ischemic brain infarction and neuronal apoptosis and necrosis in a PPARgamma dependent manner. 15d-PGJ2 may play a role in controlling acute brain damage induced by ischemia-reperfusion.

Adenoviridae↗

PubMed1981

Myocardial composition and function in diabetes. The effects of chronic insulin use.

This study was undertaken in an animal model of mild diabetes to determine if provision of chronic insulin replacement during postprandial hyperglycemia may modify the abnormalities of myocardium. Group 1 served as controls with normal glucose tolerance by intravenous testing. Two additional groups were made diabetic with low doses of alloxan. Diabetic animals of Group 2 were untreated (n = 6). Group 3 animals (n = 6) received regular insulin daily to reduce postprandial hyperglycemia. After one year with maintained body weight, the animals were studied in the intact anesthetized state using the indicator dilution technique for left ventricular volume determinations. Basal left ventricular function and contractility were similar to normals in both diabetic groups. During intraventricular infusion of saline, end-diastolic pressure rose to higher levels in untreated diabetes (14.8 +/- 2 mm Hg) than normals (8.8 +/- 0.84), despite similar basal levels. Insulin treatment was associated with higher filling pressures than in group 1 as well as reduced end-diastolic volume response. Collagen concentrations were enhanced an average of 50% in layers from the inner to outer myocardium in both untreated and treated diabetics, associated with sodium and water accumulation. Since hypertrophy was not present, the diminished compliance appeared related to increased collagen levels. On electron microscopy, the subcellular organelles of the cardiac cell appeared normal in both diabetic groups. Thus, collagen accumulation and abnormal myocardial function in this model of diabetes is not affected by control of postprandial hyperglycemia, but a potential role for sustained hormone replacement is not excluded.

Animals↗

PubMed1993

Mice expressing a bovine basic fibroblast growth factor transgene in the brain show increased resistance to hypoxemic-ischemic cerebral damage.

BACKGROUND AND PURPOSE: Cerebral intraventricular infusion of acidic or basic fibroblast growth factor has been shown to attenuate ischemic damage to hippocampal CA1 neurons in the gerbil. The purpose of the present study was to determine if the basic fibroblast growth factor transgenic mouse has an enhanced ability to resist the effects of severe cerebral hypoxemia-oligemia. METHODS: Mice that were transgenic for bovine basic fibroblast growth factor were exposed to right carotid artery ligation, hyperglycemia, and 20 minutes of 1% carbon monoxide. After 5 days' recovery, brains were examined for histological damage. RESULTS: Counts of CA1 neurons in the right hippocampus showed a significantly higher number of neurons per millimeter CA1 in hypoxic-ischemic transgenic mice compared with nontransgenic controls (transgenic, 260 +/- 33; nontransgenic, 151 +/- 37 neurons per millimeter CA1; P < .05). CONCLUSIONS: The results indicate that basic fibroblast growth factor transgenic mice, as judged by CA1 hippocampal neuronal survival, have an enhanced ability to resist the effects of a complex hypoxic-ischemic cerebral insult.

Animals↗

PubMed1995

Global incomplete cerebral ischemia produces predominantly cortical neuronal injury.

BACKGROUND AND PURPOSE: We determined the neuropathologic damage in a canine model of global incomplete ischemia commonly used in a variety of physiological experiments. METHODS: We induced 20 minutes of incomplete ischemia in dogs (n = 9) by increasing intracranial pressure via intraventricular infusion of artificial cerebrospinal fluid to maintain a cerebral perfusion pressure of 10 mm Hg while keeping body temperature at 38 degrees C during and immediately after ischemia. After a 7-day recovery period, animals were perfusion-fixed for neuropathology. In hematoxylin and eosin preparations, ischemic neuronal injury was assessed, neurons were counted, and percentage of cell damage was determined. RESULTS: No focal neurological deficits or overt seizures were observed during the 7-day recovery period. In superior temporal gyrus, 49 +/- 11% and 70 +/- 10% damage (mean +/- SEM) was observed in layer III pyramidal cells in the crown and sulcus, respectively. All neocortical regions examined showed neuronal damage in layers III and/or V. In hippocampus, 59 +/- 11% damage of pyramidal neurons occurred in CA1, with dorsal (septal) hippocampus showing more injury than ventral (temporal) portions. The caudate nucleus (head) exhibited 27 +/- 7% neuronal injury. In cerebellar cortex (anterior lobule), 70 +/- 7% damage of Purkinje cells occurred, but different folia of cerebellum showed varying degrees of injury. Brain stem and thalamus were minimally affected despite reduced blood flow. Inflammatory changes (leukocytic infiltration and neuronal incrustations) were observed, but only when neuronal degeneration was severe. Pancellular necrosis and infarction did not occur. CONCLUSIONS: This animal model of ischemia causes reproducible neuronal injury primarily in cortical regions without pancellular necrosis and infarction. Damage to subcortical areas is less severe than to cortical areas, despite comparable reductions in regional cerebral blood flow. Therefore, in the presence of regionally uniform but incomplete cerebral ischemia, neocortical and hippocampal pyramidal neurons and cerebellar cortical Purkinje cells are more likely than subcortical neurons to degenerate; alternatively, pyramidal and Purkinje neurons degenerate before neostriatal neurons in this model. This neuronal degeneration may represent an intrinsic cellular mechanism without major contribution of cytotoxic pathways associated with inflammation.

Animals↗

PubMed2006

Antisense oligonucleotide therapy for neurodegenerative disease.

Neurotoxicity from accumulation of misfolded/mutant proteins is thought to drive pathogenesis in neurodegenerative diseases. Since decreasing levels of proteins responsible for such accumulations is likely to ameliorate disease, a therapeutic strategy has been developed to downregulate almost any gene in the CNS. Modified antisense oligonucleotides, continuously infused intraventricularly, have been demonstrated to distribute widely throughout the CNS of rodents and primates, including the regions affected in the major neurodegenerative diseases. Using this route of administration, we found that antisense oligonucleotides to superoxide dismutase 1 (SOD1), one of the most abundant brain proteins, reduced both SOD1 protein and mRNA levels throughout the brain and spinal cord. Treatment initiated near onset significantly slowed disease progression in a model of amyotrophic lateral sclerosis (ALS) caused by a mutation in SOD1. This suggests that direct delivery of antisense oligonucleotides could be an effective, dosage-regulatable means of treating neurodegenerative diseases, including ALS, where appropriate target proteins are known.

Animals↗

PubMed2006

Wildtype epidermal growth factor receptor (Egfr) is not required for daily locomotor or masking behavior in mice.

BACKGROUND: Recent studies have implicated the epidermal growth factor receptor (EGFR) within the subparaventricular zone as being a major mediator of locomotor and masking behaviors in mice. The results were based on small cohorts of mice homozygous for the hypomorphic Egfrwa2 allele on a mixed, genetically uncontrolled background, and on intraventricular infusion of exogenous EGFR ligands. Subsequenlty, a larger study using the same genetically mixed background failed to replicate the original findings. Since both previous approaches were susceptible to experimental artifacts related to an uncontrolled genetic background, we analyzed the locomotor behaviors in Egfrwa2 mutant mice on genetically defined, congenic backgrounds. METHODS: Mice carrying the Egfrwa2 hypomorphic allele were bred to congenicity by backcrossing greater than ten generations onto C57BL/6J and 129S1/SvImJ genetic backgrounds. Homozygous Egfrwa2 mutant and wildtype littermates were evaluated for defects in locomotor and masking behaviors. RESULTS: Mice homozygous for Egfrwa2 showed normal daily locomotor activity and masking indistinguishable from wildtype littermates at two light intensities (200-300 lux and 400-500 lux). CONCLUSION: Our results demonstrate that reduced EGFR activity alone is insufficient to perturb locomotor and masking behaviors in mice. Our results also suggest that other uncontrolled genetic or environmental parameters confounded previous experiments linking EGFR activity to daily locomotor activity and provide a cautionary tale for genetically uncontrolled studies.

Journal Article↗

PubMed2000

Noninvasive detection of changes in cerebral blood flow by near-infrared spectroscopy in a piglet model of hydrocephalus.

Formulation of rational interventions in infantile hydrocephalus is limited by the inability to monitor cerebral hemodynamics quantitatively, continuously, and noninvasively. Near-infrared spectroscopy (NIRS) measures changes in cerebral concentration of oxygenated and deoxygenated hemoglobin (HbO(2) and Hb); HbD is the derived difference between HbO(2) and Hb. Our previous work showed that HbD reflected cerebral blood flow (CBF) measured by radioactive microspheres in a piglet model of systemic hypotension. This study was designed to determine whether NIRS detected important changes in cerebral perfusion and oxygenation in a piglet model of hydrocephalus and whether changes in HbD accurately reflected changes in CBF. Acute hydrocephalus was produced in neonatal piglets by intraventricular infusion of "mock cerebrospinal fluid." Intracranial pressure (ICP) was maintained for several minutes at approximately 10, 20, and 30 mm Hg above the baseline ICP. CBF was measured in cerebral cortex, white matter, and basal ganglia at each ICP by radioactive microspheres. Changes in HbO(2) and Hb were measured continuously by NIRS. Cerebral perfusion pressure declined with increasing ICP, and this decline was accompanied by significant decreases in HbD measured by NIRS and CBF measured by radioactive microspheres. There was a strong correlation between changes in HbD and individual changes in CBF in cerebral cortex, white matter, and basal ganglia (all p < 0.0001). This study demonstrates that changes in HbD reflect changes in CBF over a wide range of ICP in a model of acute hydrocephalus. This reproducible and easily obtained measurement by NIRS could facilitate considerably decisions concerning therapeutic interventions.

Animals↗

PubMed1988

Electrical stimulation of ascending noradrenergic tracts in the midbrain: suppression of steroid-induced luteinizing hormone release.

This study examined the effects of electrical stimulation of the dorsal and ventral ascending noradrenergic tracts in the central nervous system [dorsal (DNT) and ventral (VNT) noradrenergic tracts] during an ongoing LH surge induced by ovarian steroids. A bipolar electrode was implanted in the midbrain of ovariectomized rats, in the region of either the DNT or VNT. One week later the rats were given estradiol benzoate (10 micrograms/100 g BW), followed 3 days later by an injection of progesterone (2 mg) at 1100 h. This steroid treatment resulted in a LH surge in the afternoon which peaked at approximately 1800 h. Biphasic electrical stimulation (50-100 microA; 400 musec; 30 Hz) was applied to the conscious unrestrained rats for 1 h beginning at 1600 h. Electrical stimulation of the DNA (n = 10) for 1 h resulted in significantly lower LH levels at 1700 h. Similar electrical stimulation of the VNT (n = 8) also markedly suppressed LH release at 1700 h. Electrical stimulation of brain sites close to but outside the DNT or VNT were ineffective. After the cessation of electrical stimulation, LH levels began to rise again and at 1900 h were not significantly different from levels in the control rats. To determine if the recovering LH surge could be interrupted further, the effects of a second electrical stimulating session, 2 h after the first one, was investigated in other groups of animals. As expected, electrical stimulation of either the DNT or VNT between 1600 and 1700 h resulted in a transient suppression of the steroid-induced LH surge. The mean LH levels of these animals were on the rise between 1700 and 1900 h. Dramatically, a second electrical stimulation applied to the DNT or VNT from 1900-2000 h again inhibited LH release. Thus, the LH release pattern in these twice-stimulated rats was significantly different from that in either the nonstimulated controls or animals that had received only one electrical stimulation session (at 1600 h). Treatment of the rats with an alpha-adrenergic blocker (phenoxybenzamine) reversed the inhibitory effect of DNT activation on the LH surge. Treatment with a beta-adrenergic blocker (propranolol) or a dopamine antagonist (pimozide) was ineffective. These data demonstrate that, similar to intraventricular infusion of norepinephrine, activation of the ascending norepinephrine fibers results in interruption of the steroid-induced LH surge.

Animals↗

PubMed1976

Prostaglandin-induced release of anterior pituitary hormones: structure-activity relationships.

Prostaglandins (PG's) of the E, F, A, or B series were infused into a lateral ventricle of the brain of adult male rats, and the efficacy of each PG to stimulate the discharge of LH, prolactin, and TSH from the pituitary gland was determined. PGE2, PGF2alpha, and PGF2beta were found to be potent stimulators of LH release. The release was considerably less when PGE1, PGF1beta, PGA2, or PGB2 was infused. The basal release of LH was not altered by infusion of PGF1alpha, PGA1, PGB1, or the control solution. It is suggested that the cis double bond in the 5,6 position and the 11-hydroxyl group are essential for the LH releasing activity of PG's and that these functional groups may be of importance for activation of a receptor at the level of the brain. Prolactin secretion was stimulated 6 to 7-fold by the infusion of 5 mug of PGE2, but 20 mug had no stimulatory effect. PGF2beta caused a 3 to 4-fold increase in basal plasma prolactin concentration and was the only PG tested other than PGE2 that stimulated prolactin release. None of the PG's infused intraventricularly affected TSH secretion.

Animals↗

PubMed1976

Participation of serotonin in the phasic release of LH. I. Evidence from pharmacological experiments.

Subcutaneous implantation of a silastic tubing containing crystalline estradiol in castrated female rats results in a circadian rhythm of LH release. Under such conditions, blockade of serotonin (5-HT) biosynthesis by p-chlorophenylalanine (PCPA) completely inhibits the afternoon elevation of plasma LH. Gonadotropin peaks remain inhibited as long as the concentration of the transmitter is effectively depleted. Intraperitoneal administration or intraventricular infusion of minute doses of the immediate precursor of the amine, 5-hydroxytryptophan (5-HTP), results in the reappearance of the next afternoon rise of plasma gonadotropin, whenever hypothalamic levels of 5-hydroxyindole acetic acid (5-HIAA), the main metabolite of 5-HT, are significantly increased over their value in PGPA-treated animals. The administration of methiothepin, a 5-HT receptor blocker, 9 hours of more prior to the next expected LH rise, similarly inhibits the cycle, whereas a dopamine receptor inhibitor has no effect under the same time conditions. We have concluded that serotoninergic neuron systems can have a positive, permissive effect on the transfer of neural information resulting in phasic gonadotropin release; this action of the amine is different from, but not contradictory to, the known inhibitory effect of 5-HT on the release of LHRH from the median eminence.

Animals↗

PubMed1993

An experimental study of cerebrovascular resistance, pressure transmission, and craniospinal compliance.

To successfully match the treatment to the cause for raised intracranial pressure (ICP) after a severe head injury, it is important to know the underlying mechanism at a given moment for the raised pressure. In particular, it is important to distinguish between active cerebral vasodilation, indicating functional autoregulation, and a passive vascular dilation as the cause for raised ICP. An experimental study was performed in feline models of diffusely raised ICP (n = 6), of active arterial vasodilation caused by arterial hypercarbia (n = 6), and of passive arterial dilation caused by pharmacologically induced arterial hypertension (n = 6) to determine if wave form analysis of ICP can distinguish active from passive arteriolar vasodilation. Pulsatile pressure transmission from the blood pressure pulse to the ICP pulse (cerebrovascular pressure transmission [CVPT]), cerebrovascular resistance, and craniospinal compliance were measured simultaneously at each level of raised ICP, arterial hypercarbia, and arterial hypertension. Arterial hypercarbia, caused by both 5 and 10% inspired CO2 increased low-frequency CVPT, which was followed by an increasingly negative phase shift between the blood pressure and ICP wave form (P < 0.05). Diffusely raised ICP caused by intraventricular infusion of mock cerebrospinal fluid caused increased low-frequency CVPT (P < 0.01) but resulted in no overall change in phase shift, although the sign of the phase shift remained negative. After arterial hypertension, caused by the infusion of angiotensin II, where there was loss of myogenic tone, an increased low-frequency CVPT was accompanied by a positive phase shift (P < 0.01). These data demonstrate it may be possible to distinguish active arteriolar vasodilation from a passive loss of autoregulatory vascular tone through simultaneous measurement of the low-frequency CVPT and phase shift. Analysis of the ICP wave form provides information relevant to the management of raised ICP.

Animals↗

PubMed1994

The role of brain-derived neurotrophic factor in transient forebrain ischemia in the rat brain.

Brain-derived neurotrophic factor (BDNF) may play a role in the pathophysiology of neuronal cell death after cerebral ischemia. We investigated alterations in BDNF gene expression and the effect of BDNF on neuronal death after transient forebrain ischemia in the rat brain. Transient forebrain ischemia was induced by occlusion of the bilateral common carotid arteries and by producing systemic hypotension for 8 minutes. The alterations in the BDNF messenger ribonucleic acid content in the hippocampus and the cerebral cortex were examined by Northern blot analysis, using a phosphorus-32-labeled mouse BDNF complementary deoxyribonucleic acid probe. Recombinant Chinese hamster ovary cells with BDNF-secreting capacity were established by expression vector transfection with BDNF complementary deoxyribonucleic acid. The effect of BDNF on neuronal death in the hippocampal CA1 region after ischemia was then examined by using a continuous intraventricular infusion of 200 microliters of normal (Group II, n = 6) or 30-times concentrated recombinant Chinese hamster ovary cell culture medium containing BDNF (Group IV, n = 6). Normal (Group I, n = 6) or 30-times concentrated (Group III, n = 6) Chinese hamster ovary cell culture medium, not including BDNF complementary deoxyribonucleic acid, was infused into the same ischemic brains, which served as controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2003

Recombinant tissue plasminogen activator in the treatment of intraventricular hemorrhage secondary to periventricular arteriovenous malformation before surgery: case report.

OBJECTIVE AND IMPORTANCE: Intraventricular hemorrhage (IVH) is known to cause acute obstructive hydrocephalus, refractory elevated intracranial pressures (ICPs), and lowered cerebral perfusion pressures, leading to cortical ischemia. Frequent obstruction of external ventricular drains as a result of thrombus is a recurring theme. We present a case of IVH secondary to periventricular arteriovenous malformation (AVM) that was not visible at admission angiography and was treated by intraventricular infusion of recombinant tissue plasminogen activator before surgical intervention. CLINICAL PRESENTATION: An 11-year-old boy presented with acute onset of headache followed by two seizures, loss of consciousness, decerebration, right temporal hematoma, IVH, and acute obstructive hydrocephalus. INTERVENTION: A right external ventricular drain was placed but functioned poorly. ICP could not be controlled by conventional methods. Five milligrams of recombinant tissue plasminogen activator was injected into the ventricular system via the external ventricular drain. This was repeated daily for 4 days. This treatment resulted in progressive improvement in ICP and clinical status. Once the clot partially cleared, magnetic resonance imaging and magnetic resonance angiography suggested the presence of a right periventricular arteriovenous malformation, which was confirmed by angiography and subsequently resected. CONCLUSION: Recombinant tissue plasminogen activator is effective in resolving IVH causing obstructive hydrocephalus and uncontrollable ICP posing a life-threatening situation, secondary to ruptured arteriovenous malformation, before surgical intervention.

Cerebral Angiography↗

PubMed2002

Effect of prodynorphin-derived opioid peptides on the ovulatory luteinizing hormone surge in the proestrous rat.

The objective of this study was to determine whether prodynorphin-derived opioid peptides could block the spontaneous luteinizing hormone (LH) surge and ovulation, and if so, whether this inhibitory action was mediated through kappa-opioid receptors. Various doses of dynorphin peptides (dynorphin A(1-17), dynorphin A(1-8), dynorphin B, alpha- and beta-neoendorphin) were infused into the brain through third-ventricle cannulae in rats between 1330-1800 h on proestrus. Each dynorphin peptide blocked the LH surge and ovulation in a dose-dependent manner. Dynorphin A(1-17) and A(1-8) were equally effective in producing these actions, and more potent than either dynorphin B or alpha- or beta-neoendorphin. U50,488H, a specific kappa-opioid receptor agonist, also blocked the LH surge and ovulation. When a mixture of five dynorphin peptides was infused intraventricularly, each at a dose that inhibited the LH surge, both the surge and ovulation were blocked. However, when norbinaltorphimine, a specific kappa-opioid receptor antagonist, was coinfused with the mixture of dynorphin peptides, the LH surge and ovulation were fully restored. These results demonstrate that prodynorphin-derived opioid peptides, acting through kappa-opioid receptors, can block the LH surge and ovulation. Dynorphin A(1-17) and A(1-8) are the most potent in this regard.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed2004

Aminopyridazines attenuate hippocampus-dependent behavioral deficits induced by human beta-amyloid in a murine model of neuroinflammation.

The importance of glial cell-driven neuroinflammation in the pathogenesis and progression of Alzheimer's disease (AD) led us to initiate a drug discovery effort targeting the neuroinflammatory cycle that is characteristic of AD. We used our synthetic chemistry platform focused on bioavailable aminopyridazines as a new chemotype for AD drug discovery to develop novel, selective suppressors of key inflammatory and oxidative pathways in glia. We found that MW01-070C, an aminopyridazine that works via mechanisms distinct from NSAIDs and p38 MAPK inhibitors, attenuates beta-amyloid (Abeta)-induced neuroinflammation and neuronal dysfunction in a dose-dependent manner, and prevents Abeta-induced behavioral impairment. In vivo data were obtained with a murine model that uses intraventricular infusion of human Abeta1-42 peptide and replicates many of the hallmarks of AD pathology, including neuroinflammation, neuronal and synaptic degeneration, and amyloid deposition. The quantifiable endpoint pathology is robust, reproducible, and rapid in onset. Our results provide a proof of concept that targeting neuroinflammation with aminopyridazines is a viable AD drug discovery approach that has the potential to modulate disease progression and document the utility of this mouse model for preclinical screening of compounds targeting AD-relevant neuroinflammation and neuronal death.

Alzheimer Disease↗

PubMed2002

Disruption of neurogenesis in the subventricular zone of adult mice, and in human cortical neuronal precursor cells in culture, by amyloid beta-peptide: implications for the pathogenesis of Alzheimer's disease.

The adult mammalian brain contains populations of stem cells that can proliferate and then differentiate into neurons or glia. The highest concentration of such neural progenitor cells (NPC) is located in the subventricular zone (SVZ) and these cells can produce new olfactory bulb and cerebral cortical neurons. NPC may provide a cellular reservoir for replacement of cells lost during normal cell turnover and after brain injury. However, neurogenesis does not compensate for neuronal loss in age-related neurodegenerative disorders such as Alzheimer's disease (AD), suggesting the possibility that impaired neurogenesis contributes to the pathogenesis of such disorders. We now report that amyloid beta-peptide (Abeta), a self-aggregating neurotoxic protein thought to cause AD, can impair neurogenesis in the SVZ/cerebral cortex of adult mice and in human cortical NPC in culture. The proliferation and migration of NPC in the SVZ of amyloid precursor protein (APP) mutant mice, and in mice receiving an intraventricular infusion of Abeta, were greatly decreased compared to control mice. Studies of NPC neurosphere cultures derived from human embryonic cerebral cortex showed that Abeta can suppress NPC proliferation and differentiation, and can induce apoptosis. The adverse effects of Abeta on neurogenesis were associated with a disruption of calcium regulation in the NPC. Our data show that Abeta can impair cortical neurogenesis, and suggest that this adverse effect of Abeta contributes to the depletion of neurons and the resulting olfactory and cognitive deficits in AD.

Amyloid beta-Peptides↗

PubMed2004

Consolidation of fear extinction requires protein synthesis in the medial prefrontal cortex.

Extinction of conditioned fear is thought to form a long-term memory of safety, but the neural mechanisms are poorly understood. Consolidation of extinction learning in other paradigms requires protein synthesis, but the involvement of protein synthesis in extinction of conditioned fear remains unclear. Here, we show that rats infused intraventricularly with the protein synthesis inhibitor anisomycin extinguished normally within a session but were unable to recall extinction the following day. Anisomycin-treated rats showed no savings in the rate of re-learning of extinction, consistent with amnesia for extinction training. The identical effect was observed when anisomycin was microinfused into the medial prefrontal cortex (mPFC) but not the insular cortex. Furthermore, we observed that extinction training increased c-Fos levels in the mPFC but not in the insular cortex, consistent with extinction-induced gene expression in the mPFC. These findings extend previous lesion and unit-recording data by demonstrating that the mPFC is a critical storage site for extinction memory, rather than simply a pathway for expression of extinction. Understanding consolidation of fear extinction could lead to new treatments for anxiety disorders in which fear extinction is thought to be compromised.

Animals↗