Donna M. Byers

Gene expression following traumatic brain injury in humans : analysis by microarray

Global changes in gene expression were analyzed in pericontusional tissue taken during surgery from 4 patients with traumatic brain injury (TBI), in cerebral infarction tissue from a patient with vasculitis and in normal brain tissue resected during craniotomy for meningioma. Of approximately 1,200 genes showing some level of expression by cDNA microarray hybridization, 104 ( approximately 8%) showed differential expression in traumatized tissue. Genes controlling transcriptional regulation, intermediary and energy metabolism, signal transduction, and intercellular adhesion and recognition were differentially affected most often. Four genes previously shown to be associated with TBI (c-Fos, Jun B, HSP70, and Zif/268) were all found to be up-regulated in at least one TBI patient. Thus, the robust response to TBI of several immediate early genes is confirmed, and a longer list of candidate genes from other functional categories is suggested for further studies aimed at understanding the molecular and cellular consequences of TBI.

Sex and diet affect the behavioral response of rats to chronic mild stressors

To investigate the interaction between sex, stressors, and dietary choice in rats, a preferred diet under the influence of chronic mild stressors was empirically determined to consist of soybeans and cookies in addition to lab chow. This preferred mixed diet was then tested for its influence on several behavioral tests at the end of prolonged exposure to the potential stressors. Rats of both sexes decreased their frequency of rearing but increased their attention to novelty in response to stressors. In the elevated plus maze, diet interacted with exposure to stressors to influence time spent in the open arm in females but not males. In the forced swim test, females but not males fed the mixed diet showed increased immobility, whether exposed to stressors or not. Finally, females but not males showed a differential effect of diet under stressors on the sucrose preference test, but this result was confounded by estrus cycling, demonstrating the importance of this factor in analyzing behavior in females. These results suggest that male and female rats differ in their susceptibility to the behavioral-modifying influences of stressors. And to the extent that diet serves as a coping mechanism, it does so differently in males and females.

Circadian-dependent effect of melatonin on dopaminergic D2 antagonist-induced hypokinesia and agonist-induced stereotypies in rats

Although a melatonin/dopamine relationship has been well established in nonmotor systems wherein dopamine and melatonin share an antagonist relationship, less clear is the role melatonin may play in extrapyramidal dopaminergic function. Therefore, the purpose of the present experiments was to examine the relationship between melatonin and the dopaminergic D2 receptor system and behavior. Hypokinesia was induced in male Sprague-Dawley rats with fluphenazine (D2 antagonist, 0.4 mg/kg ip) and stereotypies with apomorphine (D2 agonist, 0.6 mg/kg sc) during the light (1200 h) and dark (2200 h) phases. As expected, fluphenazine induced severe hypokinesia during the light phase (482 +/- 176 s); however, unexpectedly, fluphenazine-induced hypokinesia during the dark was almost nonexistent (25 +/- 6 s). Furthermore, melatonin treatment (30 mg/kg ip) produced a strong interaction with fluphenazine in that it reduced fluphenazine-induced hypokinesia by nearly 80% in the light (112 +/- 45 s) but paradoxically increased the minimal fluphenazine-induced hypokinesia in the dark by more than 60% (70 +/- 17 s). Melatonin also reduced apomorphine-induced stereotypies by nearly 40% in the light but had no effect in the dark. Taken together, these data show (1) a strong and unexpected nocturnal effect of fluphenazine on hypokinesia and (2) provide support for an antagonistic melatonin/dopaminergic interaction in the context of motor behavior and D2 receptor function which appears to be critically dependent on the light/dark status of the dopaminergic system.

Chronic Mild Stressors and Diet Affect Gene Expression Differently in Male and Female Rats

While depression is reportedly more prevalent in women than men, a neurobiological basis for this difference has not been documented. Chronic mild stress (CMS) is a widely recognized animal model, which uses mild and unpredictable environmental stressors to induce depression. Studies of chronic stress, mainly in males, have reported an increase in the relative intake of “comfort food” as a means of counteracting the effects of stress. This study was designed to test the hypothesis that genes for certain neurotrophic factors, stress markers, and appetite regulators would be expressed differentially in male and female rats exposed to chronic, mild stressors with access to a preferred diet. Gene expression for neuropeptide Y was upregulated in females purely in response to stressors, whereas that for the epidermal growth factor receptor (EGFR) and arginine vasopressin (AVP) in males and fatty acid synthase (FASN) in females responded primarily to diet. Genes for brain-derived neurotrophic factor (BDNF), AVP, and the cocaine–amphetamine regulator of transcription (CART) in males, and leptin in females, showed a significant response to the interaction between stressors and diet. Every affected gene showed a different pattern of expression in males and females. This study confirms the intimate relationship between dietary intake and response to stress at the molecular level, and emphasizes the sex- and gene-specific nature of those interactions. Therefore, it supports a neurobiological basis for differences in the affective state response to stress in males and females.

Novel odors affect gene expression for cytokines and proteinases in the rat amygdala and hippocampus.

Olfaction in rodents provides an excellent modality for the study of cellular mechanisms of information processing and storage, since a single occurrence of precisely timed stimuli has high survival value. We have followed up preliminary evidence of cytokine and proteinase involvement in normal (as opposed to pathologically-induced) brain plasticity by surveying for the presence of these factors in the olfactory circuitry of the rat. Genes for 25-30 common cytokines and their receptors, and over 30 cell matrix and adhesion molecules were found to be expressed across the olfactory bulb, insular cortex, amygdala, and dorsal hippocampus. We then measured by real-time PCR the transcriptional expression of seven of these genes following a one-time exposure to the novel odor of blueberry bars or cornnuts, in contrast to presentation of the familiar odor of lab chow. In the amygdala significant up-regulation of interleukin-1 receptor 1 (IL1r1), interleukin-4 receptor (IL4r), fibroblast growth factor 13 (FGF13), and cathepsin-H (CtsH) was observed in males in response to the odor of cornnuts only. Changes were less consistent and widespread in the hippocampus, but were again sex specific for three genes: cathepsin-L (CtsL), matrix metalloproteinase-14 (MMP-14) and MMP-16. Our results show that transcription for several specific cytokines, growth factors, and proteinases responds to a one-time exposure to a novel odor, in a manner that tends to be region- and sex-specific. This suggests considerable variation in the way that olfactory information is processed at the cellular level in different brain regions and by the two sexes.

Ganglioside patterns mature at different rates in functionally related subregions of the rat pons.

Gangliosides are known to be developmentally regulated and regionally variable, but these variations have not been shown to occur among precisely defined nuclei of the brain in relation to either aging or function. We have sought to correlate changes in ganglioside distribution with age-related changes in highly specific brain regions known to control a common function, the regulation of rapid eye movement sleep architecture. Gangliosides were extracted and quantified from micropunched regions of the locus coeruleus, dorsal raphe, laterodorsal tegmentum, pedunculopontine tegmentum and the general region of the pons containing these nuclei in young adult (3 months), adult (12 months), and aged (24 months) rats. The ganglioside distribution patterns were generally characteristic of the pons as a whole, but showed a high level of differentiation in time course at specific anatomical sites.