Stine Söderström

Changes in brain nerve growth factor levels and nerve growth factor receptors in rats exposed to environmental enrichment for one year

This study examined the effects of long-term differential rearing on levels of brain nerve growth factor, its receptors, and their relationships to cognitive function. Adult rats (two months old) were placed into either enriched or standard housing conditions where they remained for 12 months. Animals from the enriched condition group had significantly higher levels of nerve growth factor in hippocampus, visual and entorhinal cortices compared with animals housed in isolated condition. Immunohistochemical analysis of brain tissue from the medial septal area revealed higher staining intensity and fibre density with both the low-affinity and the high-affinity nerve growth factor receptors. Enriched rats performed better than isolated rats in acquisition of spatial learning and had lower locomotion scores in the open field. These results provide further evidence that experimental stimulation results in increased production of trophic factors and structural reorganization in specific brain regions known to be involved in cognitive function.

Environmental influences on the central nervous system and their implications for the aging rat

Two methods of providing environmental stimulation that were introduced in the 1950s have guided much research on neurobehavioural plasticity. These are neonatal handling and environmental enrichment. Neonatal handling has been shown to permanently affect behaviour and endocrine responses. Recently this manipulation has been shown to have important influences on the aging individual, protecting the hippocampus from age-related dysfunction and neuronal loss. These effects are mediated, in part, by keeping glucocorticoid levels low. This has been characterised by, among other things, elevated expression of glucocorticoid receptors in the hippocampus. Earlier studies have failed to present convincing evidence for differences in hormonal variables between animals housed in enriched and impoverished environments, and have not consistently reported changes in the hippocampus. Recent data from our laboratories have shown that adult animals housed in enriched environments had, like neonatally-handled rats, higher expression of the gene encoding glucocorticoid receptors in the hippocampus. Taken together with the induction of NGF and NGFIA gene expression in the hippocampus of enriched animals, these results implicate genes encoding transcription factors and glucocorticoid receptors in the cascade of events leading to environmentally induced cerebral changes. In addition, these results suggest that environmental enrichment in adulthood, like neonatal handling, may have the potential to protect the aging hippocampus from glucocorticoid neurotoxicity.

Bone morphogenetic proteins and their receptors: potential functions in the brain.

Transforming growth factors‐β (TGF‐βs), activins, and bone morphogenetic proteins (BMPs) comprise an evolutionarily well‐conserved group of proteins controlling a number of cell differentiation, cell growth, and morphogentic processes during development. The superfamily of TGFβ–related genes include over 25 members in mammals several of which are expressed in the growing nervous system and serve important functions in regionalizing the early CNS. Cultured nerve cells show different responses to these factors. Recent developments have revealed that TGFβs, activins, and BMPs selectively signal to the responding cells via different hetero‐oligomeric complexes of type I and type II serine/threonine kinase receptors. The adult brain exhibits specific expression patterns of some of these receptors suggesting neuronal functions not only during development but also in the mature brain. In particular, the brain is expressing high levels of bone morphogenetic protein receptor type II (BMPR‐II), activin receptor type I (ActR‐I), and activin receptor type IIA (ActR‐II). This indicates that osteogenic protein‐1 (OP‐1/BMP‐7), BMP‐2, and BMP‐4 as well as activins may serve functions for brain neurons. Expression of the receptors partially overlaps in populations of neurons and has been shown to be regulated by brain lesions. This suggests that brain neurons may use receptors BMPR‐II and ActR‐I to sense the presence of BMPs. This may form a system parallel to the neurotrophin Trk tyrosine kinase receptors regulating neuroplasticity and brain repair. The presence of BMPs in brain is not well studied, but preliminary in situ data indicate that the BMP relatives growth/differentiation factor (GDF)‐1 and GDF‐10 are distinctly but differentially expressed at high levels in neurons expressing BMPR‐II and ActR‐I. The receptors mediating responses to these two GDFs remain, however, to be defined. Finally, recent data show that the signal from the activated type I serine/threonine kinase receptor is directly transduced to the nucleus by Smad proteins that become incorporated into transcriptional complexes. Preliminary in situ hybridization observations demonstrate the existence of different Smad mRNAs. It is concluded that BMPs and their signaling systems may comprise a novel pathway for control of neural activity and offer means for pharmacological interventions rescuing brain neurons. J. Neurosci. Res. 51:139–146, 1998. © 1998 Wiley‐Liss, Inc.

Effects of environmental enrichment on cognitive function and hippocampal NGF in the non-handled rats

In this study we examine whether exposure to differential housing after weaning would counteract the effects of postnatal handling (H) or nonhandling (NH) treatment by affecting learning and memory processes in young rats. In addition, we seek to determine if experience in enriched environment would alter hippocampal nerve growth factor (NGF) levels which is one of the factors known to be involved in the regulation of the survival and differentiation of developing basal forebrain neurones. Rats were either exposed to handling treatment, or left undisturbed starting day 1 after birth through day 21. After weaning on day 22, we exposed half of the H rats and half of the NH rats to environmental enrichment for 60 days. The other respective half of the rats was housed in isolated environmental condition (IC). Behavioural measures were taken in open field test, and spatial water maze test. Exposure to enriched environment following postnatal handling and nonhandling increased hippocampal NGF levels, and improved cognitive function in the both groups, with NH rats being more responsive to the effects of enrichment. Our results suggest that environmental enrichment has the potential to prevent or reduce the cognitive and neurochemical deficits in the adult animals associated with nonhandling.

Expression of serine/threonine kinase receptors including the bone morphogenetic factor type II receptor in the developing and adult rat brain

Abstract.The expression patterns of serine/threonine kinase receptors in the central nervous system of the developing and adult rat were studied by in situ hybridization. The recently cloned bone morphogenetic factor receptor type II (BMPR-II) was compared with the ActR-II and several type I receptors including ActR-I, ActR-IB, BMPR-IA, BMPR-IB and TβR-I. We found that these receptors are spatially and temporally regulated. As early as embryonic day 11 (E11), BMPR-II mRNA was expressed in the neuroepithelium in brain and spinal cord. At E15, the expression of ActR-II mRNA was stronger than that of BMPR-II in the spinal cord, followed in intensity by the expression of ActR-I, ActR-IB, BMPR-IA, BMPR-IB and TβR-I mRNA. The BMP type I receptors were expressed only in the ependymal epithelium and in the sympathetic ganglia at E15. Many of the examined receptor mRNAs were expressed at peak levels in the brain around birth. In the adult brain, mRNA for BMPR-II was expressed in different patterns together with ActR-II and ActR-I. Thus, BMPR-II mRNA was found in neurons of the cortex, dentate gyrus, hippocampus, habenula and substantia nigra. ActR-II, ActR-I, ActR-IB and, weakly, TβR-I were all expressed in the dentate gyrus. In contrast mRNA for BMPR-IA and BMPR-IB was not found in the adult brain. It is suggested that the expressed receptors may mediate actions of members of the TGFβ superfamily, e.g. BMPs, controlling the development and plasticity in the nervous system.

Widespread increase of nerve growth factor protein in the rat forebrain after kindling-induced seizures ☆

Nerve growth factor (NGF) protein levels were determined in various forebrain regions using a two-site immunoassay following kindling-induced seizures. In the dentate gyrus the NGF content was significantly elevated 7 days after the last seizure (to 152% of control). In the piriform and parietal cortices, maximal increases were seen at 12 h (to 261% of control) and at 24 h (to 169% of control), respectively, and the NGF content was then normalized at 7 days. The increased production of NGF might be a protective response or could be involved in plastic changes underlying kindling epileptogenesis.

Effects of neonatal stimulation on later cognitive function and hippocampal nerve growth factor.

This study examined the behavioural and physiological effects of chronic mild stress on neonatally handled and non-handled rats. Neonatally handled and non-handled rats were exposed to chronic mild stress from weaning time to 6 months of age. They were behaviourally tested at 6 months of age, and sacrificed for analysis of nerve growth factor (NGF) in the hippocampus and hypothalamus. In contrast to the reported deleterious effect of acute strong stress, mild stress appeared to stimulate production of NGF in the hippocampus and improve spatial learning in both handled and nonhandled rats. Because neonatal handling produces neuroanatomical changes in the rat hippocampus and enhances cognitive function throughout the rats life span, these results implicate hippocampal NGF in the neuroprotective effects of handling.

Embryonic expression of the mRNA for the rat homologue of the fusin/CXCR-4 HIV-1 co-receptor

We have previously cloned a human receptor recently shown to be a cofactor for entry of T-tropic HIV-1 strains into CD4+ cells, now named fusin. Stromal derived factor-1 (SDF-1) is an endogenous ligand for fusin, also called CXCR-4. Here we show the distribution of fusin/CXCR-4 mRNA during ontogeny in the rat. The onset of mRNA expression is around embryonic day 9 and the mRNA expression is high in the thymus as well as proliferative areas of the brain during development. Our results suggest: (1) that fusin/CXCR-4 might have a dual role in both brain development and the immune system; (2) that SDF-1 has a role in brain development or that additional physiological ligands exist for this receptor; (3) co-expression of CD4 and fusin/CXCR-4 may make fetuses susceptible to HIV infection during development.

Expression of serine/threonine kinase receptors in traumatic brain injury

THE aim of this study was to investigate the expression of serine/threonine kinase receptors in the brain following traumatic brain injury. We report here that, the recently cloned and characterized bone morphogenetic protein (BMP) receptor type II (BMPR-II) and the activin receptor type IA (ActR-1) Act: mRNAs were simultaneously up-regulated in neurones in the dentate gyrus 6 h after a mild cerebral contusion injury. This finding was specific for these receptors since other investigated genes (i.e. ActR-II, ActR-IB, trkB and c-fos) showed other temporal patterns. These data suggest that type I and type II receptors act together in signal transduction in vivo and that BMPs may be involved in neuronal plasticity after traumatic brain injury.

A non-invasive system for delivering neural growth factors across the blood-brain barrier: A review

Intraventricular administration of nerve growth factor (NGF) in rats has been shown to reduce age-related atrophy of central cholinergic neurons and the accompanying memory impairment, as well as protect these neurons against a variety of perturbations. Since neurotrophins do not pass the blood-brain barrier (BBB) in significant amounts, a non-invasive delivery system for this group of therapeutic molecules needs to be developed. We have utilized a carrier system, consisting of NGF covalently linked to an anti-transferrin receptor antibody (OX-26), to transport biologically active NGF across the BBB. The biological activity of this carrier system was tested using in vitro bioassays and intraocular transplants; we were able to demonstrate that cholinergic markers in both developing and aged intraocular septal grafts were enhanced by intravenous delivery of the OX-26-NGF conjugate. In subsequent experiments, aged (24 months old) Fischer 344 rats received intravenous injections of the OX-26-NGF conjugate for 6 weeks, resulting in a significant improvement in spatial learning in previously impaired rats, but disrupting the learning ability of previously unimpaired rats. Neuroanatomical analyses showed that OX-26-NGF conjugate treatment resulted in a significant increase in cholinergic cell size as well as an upregulation of both low and high affinity NGF receptors in the medial septal region of rats initially impaired in spatial learning. Finally, OX-26-NGF was able to protect striatal cholinergic neurons against excitotoxicity and basal forebrain cholinergic neurons from degeneration associated with chemically-induced loss of target neurons. These results indicate the potential utility of the transferrin receptor antibody delivery system for treatment of neurodegenerative disorders with neurotrophic substances.