Local protein translation in dendrites could be a means for delivering synaptic proteins to their sites of action, perhaps in a spatially regulated fashion that could contribute to plasticity. To directly test the functional role of dendritic translation of calcium/calmodulin-dependent protein kinase IIalpha (CaMKIIalpha) in vivo, we mutated the endogenous gene to disrupt the dendritic localization signal in the mRNA. In this mutant mouse, the protein-coding region of CaMKIIalpha is intact, but mRNA is restricted to the soma. Removal of dendritic mRNA produced a dramatic reduction of CaMKIIalpha in postsynaptic densities (PSDs), a reduction in late-phase long-term potentiation (LTP), and impairments in spatial memory, associative fear conditioning, and object recognition memory. These results demonstrate that local translation is important for synaptic delivery of the kinase and that local translation contributes to synaptic and behavioral plasticity.

SUMMARY Male behaviors require both testosterone and estrogen. Circulating testosterone activates the androgen receptor (AR) and is also converted into estrogen in the brain via aromatase. This conversion is the primary source of estrogen to the male brain. It is unclear whether testosterone and estrogen signaling interact to masculinize neural circuits. Using a genetic approach, we show extensive sexual dimorphism in the number and projections of aromatase expressing neurons. The masculinization of these cells is independent of AR but can be induced by either testosterone or estrogen, indicating a role for aromatase in sexual differentiation of these neurons. We provide evidence suggesting that aromatase is also important in activating male aggression and urine marking as these behaviors can be elicited by testosterone in males mutant for AR. Taken together with additional findings, our results suggest that aromatization of testosterone into estrogen is important for the development and activation of neural circuits that control male territorial behaviors.

SUMMARY Sex hormones such as estrogen and testosterone are essential for sexually dimorphic behaviors in vertebrates. However, the hormone-activated molecular mechanisms that control the development and function of the underlying neural circuits remain poorly defined. We have identified numerous sexually dimorphic gene expression patterns in the adult mouse hypothalamus and amygdala. We find that adult sex hormones regulate these expression patterns in a sex-specific, regionally-restricted manner, suggesting that these genes regulate sex typical behaviors. Indeed, we find that mice with targeted disruptions of each of four of these genes (Brs3, Cckar, Irs4, Sytl4) exhibit extremely specific deficits in sex specific behaviors, with single genes controlling the pattern or extent of male sexual behavior, male aggression, maternal behavior, or female sexual behavior. Taken together, our findings demonstrate that various components of sexually dimorphic behaviors are governed by separable genetic programs.

Odors detected by the vomeronasal organ or the main olfactory epithelium (MOE) trigger social behaviors in many animals. It is unknown whether MOE neurons detect cues that initiate mating or aggression. We demonstrate that mice lacking functional CNGA2 (cyclic nucleotide-gated channel alpha2), which is required for odor-evoked MOE signaling, fail to mate or fight, suggesting a broad and essential role for the MOE in regulating these behaviors.

Targeted mutagenesis in mice has shown that genes from a wide variety of gene families are involved in memory formation. The efficient identification of genes involved in learning and memory could be achieved by random mutagenesis combined with high-throughput phenotyping. Here, we provide the first report of a mutagenesis screen that has generated memory mutants in the mouse. We tested a group of N-ethyl-N-nitrosourea (ENU) mutagenized mice in the conditioned fear paradigm. We screened for both dominant and recessive mutations that caused impairments in contextual or tone fear conditioning. Heritability testing confirmed three fear conditioning mutants, i.e., Forgetful, Slowlearner, and Scatterbrain. All three have a learning or short-term memory deficit in contextual fear conditioning. Forgetful was further characterized and showed a highly specific phenotype. The contextual fear-conditioning deficit was apparent when Forgetful was trained with tone-shock pairings, but not when trained with shock alone. The deficit was not due to changes in shock sensitivity or anxiety. Forgetful was not impaired in two other memory tests (hidden platform version of Morris water maze and object recognition). Our data show that a mutagenesis screen can generate mutant mice with highly specific memory phenotypes that can supplement existing mice with targeted mutations. Mapping of Slowlearner found linkage to a region of chromosome 12 (LOD score of 6.5 close to D12Mit171), which suggests that ENU mutants should enable the positional cloning of genes involved in memory formation.Though memory is expressed at the behavioral level, it is dependent on molecular events. Knockout and transgenic mice have shown that a large number of genes are involved in memory formation (Mayford and Kandel 1999;Silva 2003;Tonegawa et al. 2003). Quantitative trait locus analysis in mice has identified many genomic regions that contribute to learning and memory (Caldarone et al. 1997;Wehner et al. 1997;Valentinuzzi et al. 1998;Steinberger et al. 2003). It has become apparent from these studies that memory formation requires the coordinated activity of a large number of genes encoding proteins involved in neurotransmission, signal transduction, regulation of gene expression, and the growth and differentiation of neuronal processes.Mutagenesis screens that combine random mutagenesis with high-throughput phenotyping provide an efficient method for genetically dissecting complex phenotypes. They can identify critical genetic components, and because of their unbiased character, can lead to the discovery of new mechanisms. Mutagenesis screens using Drosophila have revealed key insights into the genetics of learning and memory (Dubnau and Tully 1998). Complex behavioral phenotypes can also be dissected with mutagenesis screens that use model organisms more closely related to humans, as was demonstrated by the Clock mutant mouse (Vitaterna et al. 1994;King et al. 1997).Here, we provide the first report of a mutagenesis screen that has generated memory mutants ...

It has been known since antiquity that gender-specific behaviors are regulated by the gonads. We now know that testosterone is required for the appropriate display of male patterns of behavior. Estrogen and progesterone, on the other hand, are essential for female typical responses. Research from several groups also indicates that estrogen signaling is required for male typical behaviors. This finding raises the issue of the relative contribution of these two hormonal systems in the control of male typical behavioral displays. In this review we discuss the findings that led to these conclusions and suggest various genetic strategies that may be required to understand the relative roles of testosterone and estrogen signaling in the control of gender specific behavior.All animals exhibit sex differences in behavior that are characteristic of the species. Such gender typical behaviors are often used to court mates, to defend territory and other resources, and to procure food for mates and offspring. These sexual dimorphisms in behavior are often innate and can be displayed without prior social experience or training, suggesting that the neural circuits that mediate these behaviors are developmentally hardwired in the brain. Nevertheless, the display of these behaviors is tightly regulated by external sensory cues as well as internal physiological regulators such as hormones. Such dual control ensures that animals engage in these behaviors only at the appropriate time and circumstance. While we have learned much about the sensory and hormonal control of sexually dimorphic behaviors (Morris et

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