The molecular basis of CNS myelin regeneration (remyelination) is poorly understood. We generated a comprehensive transcriptional profile of the separate stages of spontaneous remyelination that follow focal demyelination in the rat CNS and found that transcripts that encode the retinoid acid receptor RXR-γ were differentially expressed during remyelination. Cells of the oligodendrocyte lineage expressed RXR-γ in rat tissues that were undergoing remyelination and in active and remyelinated multiple sclerosis lesions. Knockdown of RXR-γ by RNA interference or RXR-specific antagonists severely inhibited oligodendrocyte differentiation in culture. In mice that lacked RXR-γ, adult oligodendrocyte precursor cells efficiently repopulated lesions after demyelination, but showed delayed differentiation into mature oligodendrocytes. Administration of the RXR agonist 9-cis-retinoic acid to demyelinated cerebellar slice cultures and to aged rats after demyelination caused an increase in remyelinated axons. Our results indicate that RXR-γ is a positive regulator of endogenous oligodendrocyte precursor cell differentiation and remyelination and might be a pharmacological target for regenerative therapy in the CNS.

Extracellular signal-regulated kinases (ERK1 and 2) are synaptic signaling components necessary for several forms of learning. In mice lacking ERK1, we observe a dramatic enhancement of striatum-dependent long-term memory, which correlates with a facilitation of long-term potentiation in the nucleus accumbens. At the cellular level, we find that ablation of ERK1 results in a stimulus-dependent increase of ERK2 signaling, likely due to its enhanced interaction with the upstream kinase MEK. Consistently, such activity change is responsible for the hypersensitivity of ERK1 mutant mice to the rewarding properties of morphine. Our results reveal an unexpected complexity of ERK-dependent signaling in the brain and a critical regulatory role for ERK1 in the long-term adaptive changes underlying striatum-dependent behavioral plasticity and drug addiction.

We have generated mouse lines in which the RXRI3 gene was disrupted by homologous recombination. Approximately 50% of the RXR~ homozygous mutants died before or at birth, but those that survived appeared normal except that the males were sterile, owing to oligo-astheno-teratozoospermia. Failure of spermatid release occurred within the germinal epithelium, and the epididymis contained very few spermatozoa that, in addition, exhibited abnormal acrosomes and tails. There was a progressive accumulation of lipids within the mutant Sertoli cells, which were histochemically characterized as unsaturated triglycerides. In old mutant males, progressive degeneration of the germinal epithelium occurred, ending with the formation of acellular lipid-filled tubules. The selective expression of RXR[~ in Sertoli cells, together with the timing of appearence of the histological abnormalities, suggests that the primary defect resulting from the mutation resides in these cells.

Estrogens are powerful modulators of neuronal physiology and in humans may affect a broad range of functions, including reproductive, emotional, and cognitive behaviors. We studied the contribution of estrogen receptors (ERs) in modulation of emotional processes and analyzed the effects of deleting ER␣ or ER␤ in mice. Behavior consistent with increased anxiety was observed principally in ER␤ mutant females and was associated with a reduced threshold for the induction of synaptic plasticity in the basolateral amygdala. Local increase of 5-hydroxytryptamine 1a receptor expression in medial amygdala may contribute to these changes. Our data show that, particularly in females, there is an important role for ER␤-mediated estrogen signaling in the processing of emotional behavior. There is a strong link between estrogen and emotional disturbances in humans. Mood fluctuations, depression, irritability, and anxiety have often been associated with low levels of estradiol in postmenopausal women (1, 2), whereas estrogen replacement therapy ameliorates these psychological conditions (1-3). Reduced estrogen signaling in rodents leads to behavior indicative of increased anxiety (4, §). Little is known, however, about either the mechanisms or sites of estrogen actions in these modulatory processes, or the neurotransmitter systems involved in these regulations.In the nervous system, estrogen signals are transduced by both nuclear estrogen receptors (ER␣ and ER␤), which act as transcription factors, and by a nongenomic pathway, which has yet to be identified. Both receptors show similar patterns of expression and are found at abundance in medial amygdala, bed nucleus of stria terminalis and preoptic area, whereas in hippocampus, ER␣ is the predominant ER isotype in mouse (5). Recent analysis of reproductive and aggressive behavior in ER␣ and ER␤ null mutant mice provided the first clear evidence for a role for ERs in brain functions (6-8).High levels of estrogens have been shown to increase dendrite growth and synaptic plasticity in the rat hippocampus in vitro and in vivo (9, 10). Furthermore, the in vivo experiments revealed that estrogen enhances neuronal excitability in the hippocampus (11). In the basolateral amygdala, a structure involved in fear and anxiety, estrogens have quite the opposite effect and reduce neuronal excitability (11,12). Although the exact mode of action by which estrogen exerts its diverse effects is not clear, it is almost certain that the inhibitory neurotransmitter ␥-aminobutyric acid (GABA) is involved (13, 14, ¶). GABA is implicated in fear and anxiety, on the evidence of both pharmacological (15, 16) and gene-targeting (17, 18) experiments. Regulation of the expression of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD) by ERs (13, ¶, 19) may be crucial to modulation of GABA type A activity and, therefore, to fear and anxiety. Moreover, GABAergic tone in amygdala can be affected by serotonergic signaling (20, 21), which in turn can be downregulated by estrogen's effects on the 5-h...