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M Metzger

Publications and source records attributed to M Metzger.

At least 19 recordsLinked to original sources
PubMed2007

Treatment of new-onset type 1 diabetes with peptide DiaPep277 is safe and associated with preserved beta-cell function: extension of a randomized, double-blind, phase II trial.

BACKGROUND: Treatment with DiaPep277, a peptide derived from HSP60, has been shown to preserve beta-cell function in non-obese diabetic mouse (NOD) mice and in a trial with newly diagnosed human patients with type 1 diabetes treated over a 10-month period. This article extends the clinical trial observations to a total of 20 months of treatment to determine the safety and the effects of repeated doses of DiaPep277 on endogenous insulin secretion, metabolic control, and exogenous insulin requirements. METHODS: Thirty-five male patients (aged 16-58) with a basal C-peptide greater than 0.1 nmol/L were assigned to periodic treatment with DiaPep277 (1 mg) or placebo for a 12-month treatment and 18-month observation protocol, later extended to an additional year of treatment. Stimulated C-peptide, HbA1c, and an exogenous insulin dose were the clinical endpoints. RESULTS: At 18 months, stimulated C-peptide concentrations had fallen in the placebo group (p = 0.0005) but were maintained in the DiaPep277 group. The need for exogenous insulin was higher in the placebo group than in the DiaPep277 group. Mean HbA1c concentrations were similar in both groups. After extension of the study, patients continuing treatment with DiaPep277 and those switched from placebo to DiaPep277 manifested a trend towards a greater preservation of beta-cell function compared to patients maintained on or switched to placebo. The safety profile of DiaPep277 was similar between the treatment and placebo groups, and no drug-related adverse events occurred. CONCLUSIONS: Periodic treatment of subjects with DiaPep277 over 2 years was safe and associated preservation of endogenous insulin secretion up to 18 months was observed.

Adolescent↗
PubMed2006

Regional and cellular distribution of the extracellular matrix protein tenascin-C in the chick forebrain and its role in neonatal learning.

The juvenile brain's pronounced synaptic plasticity in response to early experience and learning events is related to the fact that the genetically pre-programmed molecular machinery mediating neuronal development and synapse formation, is activated throughout postnatal brain development and thereby can be recruited for learning and long-term memory formation. In situ hybridization and immunocytochemistry experiments revealed that tenascin-C, one candidate molecule which we suspect to be involved in neonatal learning, is expressed in the forebrain of domestic chicks around the sensitive period during which auditory filial imprinting takes place. The involvement of tenascin-C in this juvenile learning task was tested by injections of monoclonal antibodies directed to distinct domains of the tenascin-C molecule into the avian prefrontal cortex analog, the medio-rostral nidopallium/mesopallium (formerly termed medio-rostral neostriatum/hyperstriatum ventrale), a forebrain area which has been shown to be critically involved in auditory filial imprinting. Injections of monoclonal antibody Tn 68, which is directed against a cell-binding domain of the tenascin-C molecule, strongly reduced the imprinting rate, as opposed to injections of the monoclonal antibody Tn 578, which binds to a domain involved in neurite outgrowth. Double labeling immunohistochemistry revealed that tenascin-C is associated with neurons which express the Ca(2+)-binding protein parvalbumin, and displays a staining pattern highly reminiscent of perineuronal nets of the extracellular matrix. These results indicate that a distinct domain of tenascin-C is functionally involved in the juvenile learning process of filial imprinting and further suggest a critical role of a specific neuronal subpopulation.

Age Factors↗
PubMed2006

Monoaminergic markers in the optic tectum of the domestic chick.

The avian optic tectum has become a reliable model system to study the basic mechanisms that underlie the computation of visual stimuli. Many aspects of its cytoarchitecture, chemoarchitecture, connectivity and development are thoroughly characterized. However, knowledge about its monoaminergic innervation is still incomplete. As a prerequisite to understand a possible functional role of the monoaminergic neurotransmitters, the serotonergic, noradrenergic, and dopaminergic innervation of the optic tectum as well as the distribution of serotonin 2A receptors, the dopamine- and cAMP-regulated phosphoprotein DARPP-32 and calbindin D-28K was studied in domestic chicks by immunohistochemical techniques. Serotonergic, noradrenergic, and tyrosine hydroxylase positive axons and axon terminals were present in all layers of the optic tectum. Generally, the highest densities of serotonergic, noradrenergic, and tyrosine hydroxylase positive fibers were found in the superficial tectal layers 1-8, whereas only moderate densities of serotonergic, noradrenergic, and tyrosine hydroxylase positive fibers became obvious in the deep tectal layers 9-15. Serotonergic fibers were particularly abundant in layers 4, 5a and 7 and serotonin 2A receptors in layer 13. Noradrenergic fibers were densest in layers 4 and 5a, whereas tyrosine hydroxylase positive fibers showed a slightly different distribution pattern with additional dense labeling in layer 7. As revealed by double-labeling immunohistochemistry, serotonergic fibers were closely related to the cell bodies of calbindin-positive horizontal cells in layer 5b and tyrosine hydroxylase positive fibers often contacted DARPP-32+ dendritic shafts in layers 9 and 10. These findings indicate that the catecholaminergic innervation of the optic tectum consists of a noradrenergic and a dopaminergic component and that the noradrenergic, serotonergic, and dopaminergic system may be potentially involved in the modulation of retinal input in the superficial layers of the optic tectum as well as in the modulation of tectal output via the deep tectal layers.

Animals↗
PubMed2005

[Management of cardiac arrest in a German soccer stadium. Structural, process and outcome quality].

BACKGROUND: In Germany there is a lack of data about the quality of emergency medical care in mass gatherings. The following report reflects our experience with management of cardiac arrest events as an example for the most critical medical emergency in a soccer stadium. METHODS: The Fritz-Walter Stadium is a well-known soccer arena with a crowd capacity of 46,600. Emergency medical care is provided by a 2-tiered system consisting of 3 emergency physicians and 65 ambulance personnel and paramedics. Resuscitation was conducted according to the guidelines of the European Resuscitation Council and American Heart Association. RESULTS: Within 80 months, 13 witnessed cardiac arrests occurred, all in males. In each case the initial rhythm was ventricular fibrillation, 6 patients collapsed before or after the match. Basic life support was usually provided within 2 min, defibrillation and advanced life support within 4 min, 77% regained spontaneous circulation, and 62% survived without neurologic deficits. CONCLUSION: Cardiac arrest is a relatively frequent event in a soccer stadium. Due to a well organised response system, the survival rate exceeded by far the corresponding figures reported by public health systems.

Cardiopulmonary Resuscitation↗
PubMed2005

Insulin pump therapy vs. multiple daily injections in obese Type 2 diabetic patients.

AIMS: To compare the efficacy of insulin pump treatment with multiple daily injections in the treatment of poorly controlled obese Type 2 diabetic patients already receiving two or more daily injections of insulin plus metformin. METHODS: Forty obese Type 2 diabetic subjects (using insulin) were randomized to treatment with continuous subcutaneous infusion pump (CSII) (Minimed) or multiple daily insulin injections (MDI). At the end of the first 18-week treatment period, patients underwent a 12-week washout period during which they were treated with MDI plus metformin. They were then crossed-over to the other treatment for an 18-week follow-up period. Patients performed 4-point daily self blood-glucose monitoring (SBGM) on a regular basis and 7-point monitoring prior to visits 2, 8, 10 and 16. A subset of patients underwent continuous glucose monitoring using the Minimed(R) continuous glucose monitoring system (CGMS) at visits 2, 8, 10 and 16. A standard meal test was performed in which serum glucose was tested at fasting and once each hour for 6 h following a test meal. Glucose levels were plotted against time and the area under the curve (AUC) was calculated. HbA(1c), weight, daily insulin dose and hypoglycaemic episodes were recorded. RESULTS: In obese Type 2 diabetic patients already treated with insulin, treatment with CSII significantly reduced HbA(1c) levels compared with treatment with MDI. An additional CSII treatment benefit was demonstrated by reduced meal-test glucose AUC. Initial reduction of daily insulin requirement observed in CSII-treated subjects during the first treatment period was attributable to a period effect and did not persist over time. CONCLUSIONS: In the intent-to-treat analysis, CSII appeared to be superior to MDI in reducing HbA(1c) and glucose AUC values without significant change in weight or insulin dose in obese, uncontrolled, insulin-treated Type 2 diabetic subjects.

Adult↗
PubMed2003

Downregulation of TNF-alpha and VEGF expression by Sp1 decoy oligodeoxynucleotides in mouse melanoma tumor.

Melanoma tumor growth and progression are highly dependent on adequate blood supply through angiogenesis. Since several genes involved in angiogenesis revealed potential binding sites for the transcription factor Sp1, we have examined the effects of local inoculation of Sp1 decoy oligodeoxynucleotides (ODNs) on the growth of transplanted murine melanoma tumors and the expression of VEGF and TNF-alpha within these tumors. Treatment with Sp1 decoy ODNs, but not their mutated form, led to a significant increase (P=0.041) of the tumor necrotic area, as evaluated morphometrically. Tumor necrosis was associated with a significant decrease of microvascular density (P=0.012) and relative vascular area (P=0.026), as determined by counting CD34-positive vascular structures within the tumor microenvironment of Sp1 decoy ODNs and control ODN-treated tumors. RT-PCR experiments showed a strong decrease in the levels of VEGF188 and VEGF164 isoforms and a moderate decrease of TNF-alpha in Sp1 decoy-treated tumors. Taken together, our results indicate that Sp1 decoy ODNs may inhibit angiogenesis by affecting the gene expression of key players in angiogenesis such as TNF-alpha and VEGF. These findings indicate that Sp1 decoy ODNs may be a potential new therapeutic tool in antiangiogenic therapy.

Animals↗
PubMed2002

A quantitative immuno-electron microscopic study of dopamine terminals in forebrain regions of the domestic chick involved in filial imprinting.

The mediorostral neostriatum/hyperstriatum ventrale and neostriatum dorsocaudale of the domestic chick are crucially involved in filial imprinting and are major targets of mesotelencephalic dopaminergic projections. To better understand the functional role of dopamine in these forebrain regions, the ultrastructure of dopamine terminals was studied by serial section electron microscopy using immunohistochemical labeling with antibodies to tyrosine hydroxylase and dopamine. At light as well as electron microscopic level, dopamine and tyrosine hydroxylase-immunoreactive fibers were present at moderate densities in the mediorostral neostriatum/hyperstriatum ventrale and high densities in the neostriatum dorsocaudale. The frequency of tyrosine hydroxylase-immunoreactive profiles per unit area was significantly higher in the neostriatum dorsocaudale than in the mediorostral neostriatum/hyperstriatum ventrale. In both regions, tyrosine hydroxylase-immunoreactive terminals were relatively small, with mean areas of 0.55 microm(2) in the mediorostral neostriatum/hyperstriatum ventrale and 0.48 microm(2) in the neostriatum dorsocaudale. The majority of tyrosine hydroxylase-immunoreactive synapses were symmetrical (83% in the mediorostral neostriatum/hyperstriatum ventrale, 75% in the neostriatum dorsocaudale) as opposed to asymmetrical (17 and 25%, respectively), but there were also tyrosine hydroxylase-immunoreactive terminals which lacked clear synaptic specializations. The preferred targets of the synaptic tyrosine hydroxylase-immunoreactive terminals were dendritic shafts (64% in the mediorostral neostriatum/hyperstriatum ventrale, 63% in the neostriatum dorsocaudale) and less frequently dendritic spines (17 and 23%, respectively) or perikarya (19 and 14%, respectively). In both forebrain regions, immunoreactive terminals were often found in close apposition to unstained terminals making asymmetrical synapses. In conclusion, these results indicate that the ultrastructural features of dopamine terminals in the avian telencephalon are very similar to those described in mammals and that dopamine may exert its effects primarily by modulating excitatory inputs.

Animals↗
PubMed2002

Relevance of apoptosis and cell proliferation for survival of patients with dilated cardiomyopathy undergoing partial left ventriculectomy.

BACKGROUND: Cardiomyocyte apoptosis as well as proliferation have been described in congestive heart failure, but their clinical relevance remains unclear. In order to clarify whether apoptosis and cell proliferation occur in patients with idiopathic dilated cardiomyopathy and whether their degree in left ventricle fragments resected during partial left ventriculectomy has any influence on the outcome after this surgery, we compared their occurrence in four groups of patients: group A, short-term survivors (n = 18); group B, deaths within 6 months of the surgery (n = 13); group C, long-term survivors (n = 12); and Group D, deaths within 60 months (n = 19). DESIGN: Apoptotic cardiomyocytes and interstitial cells were quantified in left ventricle fragments from 31 patients with idiopathic-dilated cardiomyopathy using the TUNEL assay. Cell proliferation was quantified in parallel sections by KI-67 immunohistochemistry. RESULTS: Apoptotic cells were present in the majority of cases (n = 24) and proliferative cells in all cases. Whereas there was no significant difference regarding all parameters examined between Groups A and B, there was a highly significant difference between Groups C and D in the number of apoptotic cardiomyocytes (P = 0.012) and apoptotic interstitial cells (P = 0.006). There was no significant relationship between apoptotic cardiomyocytes and KI-67-positive cardiomyocytes, but a negative correlation between apoptotic interstitial cells and KI-67-positive interstitial cells (r = -0.383; P = 0.028). CONCLUSION: Cardiomyocyte apoptosis and proliferation occur in the majority of patients with idiopathic-dilated cardiomyopathy. High numbers of apoptotic cardiomyocytes and apoptotic interstitial cells are significantly related to a bad late outcome after partial left ventriculectomy.

Adult↗
PubMed2001

Beta-cell function in new-onset type 1 diabetes and immunomodulation with a heat-shock protein peptide (DiaPep277): a randomised, double-blind, phase II trial.

BACKGROUND: Type 1 diabetes results from autoimmune destruction of insulin-producing pancreatic beta cells. The 60 kDa heat-shock protein (hsp60) is one of the known target self antigens. An immunomodulatory peptide from hsp60, p277, arrested beta-cell destruction and maintained insulin production in newly diabetic NOD mice. We did a randomised, double-blind, phase II study of peptide treatment in patients with newly diagnosed (<6 months) type 1 diabetes. METHODS: 35 patients with type 1 diabetes and basal C-peptide concentrations above 0.1 nmol/L were assigned subcutaneous injections of 1 mg p277 and 40 mg mannitol in vegetable oil (DiaPep277; n=18) at entry, 1 month, and 6 months, or three placebo injections (mannitol in vehicle; placebo; n=17). The primary endpoint was glucagon-stimulated C-peptide production. Secondary endpoints were metabolic control and T-cell autoimmunity to hsp60 and to p277 (assayed by cytokine secretion). 31 patients completed 10 months of follow-up and were included in the intention-to-treat analysis. FINDINGS: At 10 months, mean C-peptide concentrations had fallen in the placebo group (n=16) but were maintained in the DiaPep277 group (n=15; 0.26 [SD 0.11] vs 0.93 [0.35] nmol/L; p=0.039). Need for exogenous insulin was higher in the placebo than in the DiaPep277 group (0.67 [0.33] vs 0.43 [0.17] U/kg; p=0.042). Haemoglobin A1c concentrations were low (around 7%) in both groups. T-cell reactivity to hsp60 and p277 in the DiaPep277 group showed an enhanced T-helper-2 cytokine phenotype. No adverse effects were noted. INTERPRETATION: Although this study was small, treatment of newly diagnosed type 1 diabetes with DiaPep277 seems to preserve endogenous insulin production, perhaps through induction of a shift from T-helper-1 to T-helper-2 cytokines produced by the autoimmune T cells.

Adult↗
PubMed2001

Persistent low-level engraftment of rhesus peripheral blood progenitor cells transduced with the fanconi anemia C gene after conditioning with low-dose irradiation.

The hematopoietic stem cell has long been considered an ideal target for the introduction of therapeutic genes to treat human disorders such as Fanconi anemia (FA). Although recent progress in large animal models is encouraging, application to nonmalignant conditions is limited by the perceived necessity of myeloablative conditioning. We and others have shown that very low irradiation doses are sufficient to allow significant hematopoietic engraftment in murine hosts even after the introduction of xenogeneic genes. To determine the degree of engraftment of genetically modified cells attainable with very low irradiation doses in larger animals, we employed the rhesus macaque competitive repopulation model. Four animals underwent mobilization with stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) followed by apheresis. The apheresis product was enriched for the CD34-positive fraction by immunomagnetic selection and split equally for transduction with either G1FC26, a retroviral vector carrying the Fanconi anemia complementation group C gene, or PLII, a nonexpression control retroviral vector carrying both neomycin and beta-galactosidase gene sequences modified to prevent translation. Transductions were performed daily in the presence of fresh IL-3, IL-6, SCF, and Flt-3 ligand on fibronectin-coated plates over 96 h. Animals were conditioned with a single dose of either 100 (n = 2) or 200 (n = 2) cGy and received the combined products of transduction on the following day. None of the animals experienced clinically significant neutropenia nor required the use of central line placement, transfusional support with blood products, or intravenous antibiotics. Using real-time PCR, circulating levels of genetically modified cells as high as 1% were initially detected. Stable, albeit, significantly lower levels from both vector-transduced aliquots (<0.1%) persisted beyond 12 months posttransplant in all four animals. Although not sufficient to correct the phenotype in many human disorders, stable low-level engraftment by genetically modified cells following low-intensity conditioning may prove adequate in disorders such as FA due to the selective advantage conferred upon corrected cells.

Animals↗
PubMed2000

Late developmental expression of DARPP-32 in the chick optic tectum.

Immunohistochemical techniques reveal that the dopamine- and cAMP-regulated phosphoprotein DARPP-32 is detectable in neurons of the chick optic tectum starting on embryonic day 13. The expression levels then increase steadily from embryonic day 15 through the first posthatching day. After 15 days posthatching, expression of DARPP-32 reaches the adult pattern, with many labeled cells in tectal layers 11 and 12. These cells exhibit a bipolar shape, with long processes directed both to the deep and superficial layers. These results suggest that DARPP-32 is present in specific neuronal populations of the chick tectum and that this protein may not have a function in early ontogenetic processes.

Animals↗
PubMed2000

L-NMMA (a nitric oxide synthase inhibitor) is effective in the treatment of cardiogenic shock.

BACKGROUND: The objective was to assess the safety and efficacy of L-NMMA in the treatment of cardiogenic shock. METHODS: We enrolled 11 consecutive patients with cardiogenic shock that persisted after >24 hours from admission, despite coronary catheterization and primary percutaneous transluminal coronary revascularization, when feasible, and treatment with mechanical ventilation, intraaortic balloon pump (IABP), and high doses of catecholamines. L-NMMA was administered as an IV bolus of 1 mg/kg and continuous drip of 1 mg. kg(-1). h(-1) for 5 hours. Treatment with catecholamines, mechanical ventilation, and IABP was kept constant throughout the study. RESULTS: Within 10 minutes of L-NMMA administration, mean arterial blood pressure (MAP) increased from 76+/-9 to 109+/-22 mm Hg (+43%). Urine output increased within 5 hours from 63+/-25 to 156+/-63 cc/h (+148%). Cardiac index decreased during the steep increase in MAP from 2. 0+/-0.5 to 1.7+/-0.4 L/(min. m(2)) (-15%); however, it gradually increased to 1.85+/-0.4 L/(min. m(2)) after 5 hours. The heart rate and the wedge pressure remained stable. Twenty-four hours after L-NMMA discontinuation, MAP (+36%) and urine output (+189%) remained increased; however, cardiac index returned to pretreatment level. No adverse events were detected. Ten out of eleven patients could be weaned off mechanical ventilation and IABP. Eight patients were discharged from the coronary intensive care unit, and seven (64%) were alive at 1-month follow-up. CONCLUSIONS: L-NMMA administration in patients with cardiogenic shock is safe and has favorable clinical and hemodynamic effects.

Aged↗
PubMed2000

Maternal separation followed by early social deprivation affects the development of monoaminergic fiber systems in the medial prefrontal cortex of Octodon degus.

The influence of early postnatal socio-emotional deprivation on the development of tyrosine hydroxylase- and 5-hydroxytryptamine-immunoreactive fiber innervation in the medial prefrontal cortex was quantitatively investigated in the precocial rodent Octodon degus. Forty-five-days-old degus from two groups were compared: (i) degus which were repeatedly separated from their mothers during the first three postnatal weeks and after weaning reared in complete isolation; and (ii) degus which were reared under normal undisturbed social conditions. The two monoaminergic fiber systems in the four subregions of the medial prefrontal cortex responded differentially to the deprivation. While the infralimbic cortex was the only subregion that displayed an increase in 5-hydroxytryptamine-positive fiber densities (129.2%) but no changes in tyrosine hydroxylase-immunoreactive fibers, the precentral medial (82.2%), anterior cingulate (74.6%) and prelimbic cortex (86.9%) showed significantly reduced tyrosine hydroxylase-positive fiber innervation, but no changes in 5-hydroxytryptamine-immunoreactive fiber densities. The number of tyrosine hydroxylase-positive somata in the ventral tegmental area and in the substantia nigra remained unchanged. In cortical areas the number of tyrosine hydroxylase-immunoreactive somata was increased (depending on the medial prefrontal cortex subregion between 241.8% and 398.7%) in deprived animals. This altered balance between the serotonergic and dopaminergic cortical innervation in the different subregions of the medial prefrontal cortex may reflect a counter-regulative anatomical and functional adaptation, which may be triggered by an altered activity of these transmitter systems during the phases of maternal separation and social isolation.

Animals↗
PubMed2000

High-dose intravenous isosorbide-dinitrate is safer and better than Bi-PAP ventilation combined with conventional treatment for severe pulmonary edema.

OBJECTIVE: To determine the feasibility, safety and efficacy of bilevel positive airway ventilation (BiPAP) in the treatment of severe pulmonary edema compared to high dose nitrate therapy. BACKGROUND: Although noninvasive ventilation is increasingly used in the treatment of pulmonary edema, its efficacy has not been compared prospectively with newer treatment modalities. METHODS: We enrolled 40 consecutive patients with severe pulmonary edema (oxygen saturation <90% on room air prior to treatment). All patients received oxygen at a rate of 10 liter/min, intravenous (IV) furosemide 80 mg and IV morphine 3 mg. Thereafter patients were randomly allocated to receive 1) repeated boluses of IV isosorbide-dinitrate (ISDN) 4 mg every 4 min (n = 20), and 2) BiPAP ventilation and standard dose nitrate therapy (n = 20). Treatment was administered until oxygen saturation increased above 96% or systolic blood pressure decreased to below 110 mm Hg or by more than 30%. Patients whose conditions deteriorated despite therapy were intubated and mechanically ventilated. All treatment was delivered by mobile intensive care units prior to hospital arrival. RESULTS: Patients treated by BiPAP had significantly more adverse events. Two BiPAP treated patients died versus zero in the high dose ISDN group. Sixteen BiPAP treated patients (80%) required intubation and mechanical ventilation compared to four (20%) in the high dose ISDN group (p = 0.0004). Myocardial infarction (MI) occurred in 11 (55%) and 2 (10%) patients, respectively (p = 0.006). The combined primary end point (death, mechanical ventilation or MI) was observed in 17 (85%) versus 5 (25%) patients, respectively (p = 0.0003). After 1 h of treatment, oxygen saturation increased to 96 +/- 4% in the high dose ISDN group as compared to 89 +/- 7% in the BiPAP group (p = 0.017). Due to the significant deterioration observed in patients enrolled in the BiPAP arm, the study was prematurely terminated by the safety committee. CONCLUSIONS: High dose ISDN is safer and better than BiPAP ventilation combined with conventional therapy in patients with severe pulmonary edema.

Dose-Response Relationship, Drug↗
PubMed1999

The dorsocaudal neostriatum of the domestic chick: a structure serving higher associative functions.

The dorsocaudal neostriatal (dNC) complex consists of at least three functionally distinct subregions and is part of an 'imprinting' pathway, which interconnects several forebrain regions that are known to be involved in juvenile learning. Based on its anatomical features, at least one subregion of the dNC complex, the neostriatum dorsocaudale (Ndc) may be considered as the equivalent of the mammalian polysensory association cortices. Several lines of evidence point to a role for this forebrain region in learning and memory formation. After auditory or visual imprinting changes of stimulus-evoked metabolic activities and of synaptic densities have been measured in the Ndc. Pharmacological behavioral studies revealed that the activation of NMDA receptors plays a critical role during this learning process and that NMDA receptor activation is required for the associated metabolic and synaptic changes. In addition to glutamatergic afferents, anatomical studies revealed a massive input from monoaminergic and peptidergic pathways into the dNC complex, suggesting a modulatory role for these systems during imprinting. The results presented here together with data from other avian species support the view that the dNc complex, and in particular the Ndc, plays an important role in juvenile and adult learning.

Animals↗
PubMed1999

Maternal separation and early social deprivation in Octodon degus: quantitative changes of nicotinamide adenine dinucleotide phosphate-diaphorase-reactive neurons in the prefrontal cortex and nucleus accumbens.

The influence of postnatal socio-emotional deprivation on the development of nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase-reactive neurons in prefrontal cortical areas and in subdivisions of the nucleus accumbens was quantitatively investigated in the precocious rodent Octodon degus. Forty-five-days-old O. degus from two animal groups were compared: (i) degus which were repeatedly separated from their mothers during the first three postnatal weeks and after weaning reared in complete isolation; and (ii) degus which were reared under normal undisturbed social conditions. Socially-deprived animals displayed a significant decrease of NADPH-diaphorase-containing neurons in anterior cingulate cortex (85.5%), the same tendency was observed in the infralimbic, precentral medial and prelimbic prefrontal areas. Similarly, the core region of nucleus accumbens expressed reduced NADPH-diaphorase-reactive neuron numbers in deprived animals (70%), whereas the shell region remained unchanged. Since during normal postnatal development the number of NADPH-diaphorase-reactive neurons gradually decreases in all prefrontal cortical and accumbal regions, the observed deprivation-induced changes may reflect either an excessive reduction of NADPH-diaphorase-positive neurons or a down-regulation of the enzyme in neurons that normally express it. Since some NADPH-diaphorase-containing neurons in the prefrontal cortex have been shown to be GABAergic, it is tempting to speculate that a reduction of these inhibitory neurons in the anterior cingulate cortex may result in an enhanced excitatory output activity of disinhibited projection neurons in this cortical region, including those that project to the core region of the nucleus accumbens. Our results indicate a link between early adverse socio-emotional experience and the maturation of NADPH-reactive neurons and further studies are required to analyse the functional implication for this experience-induced brain pathology.

Aging↗