Thesis (M.S.)--University of Michigan, 1991.

Thesis (M.S.)--University of Michigan, 1991.

The Dlx homeobox genes encode homeodomain transcription factors that are involved in multiple developmental aspects. In the brain, these genes take part in neuronal migration and differentiation, more precisely in the migration and differentiation of GABAergic neurons. Dysfunctions in the GABAergic system can lead to various pathological conditions, where impaired inhibitory function is one of the main causes of several neuropathies characterized by neuronal hyperexcitability. The Dlx genes are organized as bi-gene clusters and highly conserved cis-regulatory elements have been previously characterized to be fundamental for the regulation of Dlx expression in developing embryos of different vertebrates. The activity of these regulatory elements and the Dlx genes has been well studied in developmental stages of mice and zebrafish, but little is known about their activity in the adult brain. The extensive neurogenesis that takes place in the adult zebrafish brain provides an ideal platform for the visualization of mechanisms involving dlx genes during adulthood and their possible involvement in adult neurogenesis. Here we show novel information concerning the expression of dlx1a, dlx2a, dlx5a and dlx6a in the adult zebrafish brain and provide insight into the identity of cells that express dlx. We also demonstrate the involvement of dlx genes in brain regeneration and through lineage tracing, their fate determination in the adult zebrafish brain. Analyses in the adult zebrafish has revealed that all four dlx paralogs are expressed in the forebrain and midbrain throughout adulthood and expression is found in almost all areas presenting continuous proliferation. Most dlx-expressing cells present GABAergic neuronal identity in the adult forebrain where, in some areas they were identified as the Calbindin subtype. In some areas of the midbrain, especially within the hypothalamus, many dlxexpressing cell co-localized with a marker for neural stem cells. However, cells expressing dlx iii genes did not co-localize with markers for proliferating cells or for glia. Investigations during brain regeneration in response to injury in the adult zebrafish brain has revealed that dlx5a expression decreases shortly after lesion and that the dlx5a/6a bi-gene cluster, more specifically, dlx5a, is up regulated during the peak of regeneration response proposing a possible role for dlx during regeneration in adults. Studies of lineage tracing have shown the progeny of dlx1a/2a-expressing cells in adults are located within small clusters in different areas of the adult brain where they seem to become mature neurons. Our observations provide a better understanding about the role of dlx genes during adulthood, further contributing to the general knowledge of the molecular pathways involved in adult neurogenesis and regeneration in the zebrafish adult brain.

La migration des cellules souches / progénitrices neurales (CSPN) dans le cerveau adulte est cruciale pour la réparation cérébrale. Reeline (Rln) est une protéine de la matrice extracellulaire, régulant le positionnement des neurones pendant la croticogénèse. Nous révélons un rôle nouveau de Rln chez l'adulte. In vitro, Rln est chémocinétique mais pas chémoattractante. In vivo, Rln induit le détachement et la dispersion des CSNP de la zone sousventriculaire (SVZ) hors du courant rostral de migration (RMS) où elles sont sinon confinées. Rln potentialise le recrutement spontané des CSPN vers les lésions démyélinisantes où un tiers deviennent oligodendrocytaires. L'expression endogène de Rln est stimulée après lésion. Les animaux sans voie de signalisation Rln ont un recrutement réduit des CSPN vers les lésions.Ces résultats révèlent que Rln est un arbitre clef de la migration post-lésionnelle des CSPN et que permettre au CSPN de sortir du RMS est une stratégie thérapeutique prometteuse. / Neural stem/ progenitor cell (NSPC) migration in the adult brain is crucial for brain repair. Reelin (Rln) is an extracellular matrix protein regulating neuron positioning during coricogenesis. We reveal new roles of Rln in adult NSPC migration. In vitro, Rln promotes detachment, is chemokinetic but not chemoattractant. After Rln ectopic overexpression in the healthly brain, subventricular zone (SVZ) NSPC detach from the rostal migratory stream (RMS) in which they are normally restricted, and disperse in adjacent fiber tracts. Rln over-expression potentiates spontaneous cell recruitment to demyelinated lesion and one third of the NSPC recruited adopt an oligodendrocytic phenotype. Rln expression is spontaneously upregulated after lesion, and disruption of its signaling pathway results in reduced NSPC recruitment toward lesion. Our study reveals that Rln is a key player of post-lesional NSPC migration and that allowing NSPC to escape from RMS is a promising therapeutic approach

Environmental factors are known to have far reaching effects on nervous system function, and in the adult brain, it is clear that a wide range of environmental stimuli modulate cell proliferation and survival (e.g., neurogenesis). This project investigated whether social stimulation and concomitant changes in gonadal hormones can influence the proliferation of new cells in the adult brain. The adult green treefrog (Hyla cinerea)was used as the model system; studying the courtship behavior of the highly social treefrog affords a direct, quantifiable way to measure the effects of acoustic social cues and hormonal intervention on adult brain cell proliferation. Using immunohistochemistry techiques, endocrinological manipulations, and socially-relevant acoustic stimulus presentations, I report that social cues modulate cell proliferation in the brains of adult male and female H. cinerea. I first mapped the distribution of proliferative areas in the adult treefrog brain using 5-bromo-2′- deoxyuridine (BrdU) labeling. I then exposed naturally-cycling male and female treefrogs to random tones or a recording of a natural H. cinerea chorus for ten days during the breeding season. I found that male and female treefrogs that heard their conspecific chorus exhibited increased brain cell proliferation compared to animals that heard random tones. Moreover, this modulation was region-specific and occurred in those regions which reflected their presumed involvement in reproductive physiology and behavior: the preoptic area (POA) and the infundibular hypothalamus (IF). To determine the involvement of gonadal hormones in cell proliferation with and without social stimulation, I gonadectomized and implanted male and female H. cinerea with blank or steroid-filled implants. After exposing the treefrogs to the same acoustic conditions as above, I discovered that social modulation of adult cell proliferation can occur without the influence of gonadal hormones (i.e., androgens in the male and estrogen in the female). Furthermore, the results revealed that neither hormone was neurotrophic and in fact, chronically-elevated estrogen levels decreased cell proliferation in the female POA and IF. Together, these results indicate that the reception of acoustic social cues increases cell proliferation in brain regions mediating sexual behavior and endocrine regulation; furthermore, this modulation occurs in a sexually-differentiated fashion without gonadal hormone influence. / text

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