Immunomodulatory Effects of Stress and Environmental Enrichment in Long-Evans Rats (Rattus norvegicus).

Stress can influence the secretion of neuroendocrine mediators, thereby exposing immune cells to altered signaling and interactions. Here we investigated the synergetic effect of stress and environmental enrichment on the immune response of Long-Evans rats. Subjects (n = 46) were assigned to 5 treatment groups: acute compared with chronic stress with or without environmental enrichment, plus an unmanipulated control group. Animals also were classified as active, passive, and flexible copers according to back-test assessment. Rats were exposed to enrichment in an open-field containing objects in different areas for 30 min 3 times each week, thus modeling the effects of a temporary increase in environmental stimuli. Animals assigned to chronic stress groups were exposed to predator sound stressors for 30 min daily, whereas animals assigned to acute stress groups were exposed once each week. After 7 wk, a dermal punch biopsy was administered to activate the immune response, after which rats were challenged through a forced swim test. Biologic samples were collected to measure corticosterone, dehydroepiandrosterone (DHEA), oxytocin, testosterone, and the cytokines IL6 and IL10. Rats exposed to chronic stress had lower DHEA:corticosterone ratios, suggesting increased allostatic load. Enrichment exposure modulated these effects, lowering overall corticosterone and testosterone levels and increasing DHEA and oxytocin levels in animals exposed to the predator sound. The immune response was decreased in rats exposed to chronic stress, but the effect of environmental enrichment helped to mitigate the negative influence on cells producing IL6. Combining acute stress and exposure to an enriched environment returned a healthier profile in terms of both immune activation and stress regulation. By using a multidimensional scaling model, we found that a combination of 'good' stress and exposure to brief sessions of enriching stimuli can reliably predict health in Long-Evans rats.

Neuregulin-1 and erbB4 immunoreactivity is associated with neuritic plaques in Alzheimer disease brain and in a transgenic model of Alzheimer disease.

Neuregulin-1 (NRG-1) regulates developmental neuronal survival and synaptogenesis, astrocytic differentiation, and microglial activation. Given these NRG-1 actions, we hypothesized that the synaptic loss, gliosis, inflammation, and neuronal death occurring in Alzheimer disease (AD) is associated with altered expression of NRG-1 and its receptors (the erbB2, erbB3, and erbB4 membrane tyrosine kinases). We examined the expression and distribution of NRG-1 and the erbB kinases in the hippocampus of AD patients and cognitively normal controls and in transgenic mice that coexpress AD-associated mutations of the beta amyloid precursor protein (APP(K670N,M671L)) and presenilin-1 (PS1(M146L)). In the hippocampi of both control humans and wild type mice, NRG-1 and the 3 erbB receptors are expressed in distinct cellular compartments of hippocampal neurons. All 4 molecules are associated with neuronal cell bodies, but only NRG-1, erbB2, and erbB4 are present in synapse-rich regions. In AD and in the doubly transgenic mouse, erbB4 is expressed by reactive astrocytes and microglia surrounding neuritic plaques. In AD brains, microglia and, to a lesser extent, dystrophic neurites, also upregulate NRG-1 in neuritic plaques, suggesting that autocrine and/or paracrine interactions regulate NRG-1 action within these lesions. NRG-1 and erbB4, as well as erbB2, are similarly associated with neuritic plaques in the doubly transgenic mice. Thus, in AD the hippocampal distribution of NRG-1 and erbB4 is altered. The similarities between the alterations in the expression of NRG-1 and its receptors in human AD and in APP(K670N;M671L)/PS1(M146L) mutant mice suggests that this animal model may be very informative in deciphering the potential role of these molecules in AD.

Exercise protects against MPTP-induced neurotoxicity in mice.

Exercise has been shown to be potently neuroprotective in several neurodegenerative models, including 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) model of Parkinson's disease (PD). In order to determine the critical duration of exercise necessary for DA neuroprotection, mice were allowed to run for either 1, 2 or 3months prior to treatment with saline or MPTP. Quantification of DA neurons in the SNpc show that mice allowed to run unrestricted for 1 or 2months lost significant numbers of neurons following MPTP administration as compared to saline treated mice; however, 3months of exercise provided complete protection against MPTP-induced neurotoxicity. To determine the critical intensity of exercise for DA neuroprotection, mice were restricted in their running to either 1/3 or 2/3 that of the full running group for 3months prior to treatment with saline or MPTP. Quantification of DA neurons in the SNpc show that mice whose running was restricted lost significant numbers of DA neurons due to MPTP toxicity; however, the 2/3 running group demonstrated partial protection. Neurochemical analyses of DA and its metabolites DOPAC and HVA show that exercise also functionally protects neurons from MPTP-induced neurotoxicity. Proteomic analysis of SN and STR tissues indicates that 3months of exercise induces changes in proteins related to energy regulation, cellular metabolism, the cytoskeleton, and intracellular signaling events. Taken together, these data indicate that exercise potently protects DA neurons from acute MPTP toxicity, suggesting that this simple lifestyle element may also confer significant protection against developing PD in humans.

Improved gene delivery into neuroglial cells using a fiber-modified adenovirus vector.

One impediment to treating neuronal diseases is finding ways to introduce genes into specific neuroglial cell types. Here we describe the strategy for efficient gene delivery via transferrin receptor using an adenovirus bearing a peptide mimic for transferrin. The attachment of the peptide consisted of 12 amino acids on the C-terminus of adenovirus fiber protein significantly improved entry and expression of a beta-galactosidase transgene into neuroglial cells such as astrocytes, and Schwann cells. The entry of re-targeted viruses into cells depends on the attached peptide and the transferrin receptor. Furthermore, transferrin did not affect gene delivery by the engineered adenovirus, suggesting that the effectiveness of therapeutic agents targeted to the receptor would not be diminished by competition with the abundant endogenous transferrin present in the plasma. Therefore, such transduction systems hold promise for efficient delivering gene to neuroglial cells in gene therapy protocols.

Neuregulin-1beta induces neurite extension and arborization in cultured hippocampal neurons.

Neuregulin-1 (NRG-1) growth and differentiation factors and their erbB receptors are hypothesized to promote embryonic hippocampal neuron differentiation via as yet unknown mechanisms. We have found that NRG-1beta increases the outgrowth of primary neurites, neuronal area, total neurite length, and neuritic branching in E18 hippocampal neurons. NRG-1beta effects on neurite extension and arborization are similar to, but not additive with, those of brain-derived neurotrophic factor and reflect direct NRG-1 action on hippocampal neurons as these cells express the NRG-1 receptors erbB2 and erbB4, the erbB-specific inhibitor PD158780 decreases NRG-1beta induced neurite outgrowth, and NRG-1beta stimulation induces p42/44 ERK phosphorylation. Pharmacological inhibition of p42/44 ERK and protein kinase C (PKC), but not PI3K or p38 MAP kinase, inhibits NRG-1beta-induced neurite extension and elaboration. We conclude that NRG-1beta stimulates hippocampal neurite extension and arborization via a signaling pathway that involves erbB membrane tyrosine kinases (erbB2 and/or erbB4), p42/44 ERK, and PKC.