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1.
Cell ; 148(3): 596-607, 2012 Feb 03.
Article in English | MEDLINE | ID: mdl-22304924

ABSTRACT

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.


Subject(s)
Amygdala/metabolism , Gene Expression Profiling , Hypothalamus/metabolism , Sex Characteristics , Sexual Behavior, Animal , Aggression , Animals , Estrus/metabolism , Female , Male , Maternal Behavior , Mice , Ovary/metabolism , Testis/metabolism , Testosterone/metabolism
2.
Cell ; 139(1): 61-72, 2009 Oct 02.
Article in English | MEDLINE | ID: mdl-19804754

ABSTRACT

Sex hormones are essential for neural circuit development and sex-specific behaviors. Male behaviors require both testosterone and estrogen, but it is unclear how the two hormonal pathways intersect. Circulating testosterone activates the androgen receptor (AR) and is also converted into estrogen in the brain via aromatase. We demonstrate 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 in females 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-specific aggression and urine marking because these behaviors can be elicited by testosterone in males mutant for AR and in females subjected to neonatal estrogen exposure. Our results suggest that aromatization of testosterone into estrogen is important for the development and activation of neural circuits that control male territorial behaviors.


Subject(s)
Brain/metabolism , Estrogens/metabolism , Neural Pathways , Sex Characteristics , Animals , Animals, Newborn , Aromatase/metabolism , Cell Survival , Estrogens/biosynthesis , Female , Male , Mice , Neurons/metabolism , Receptors, Androgen/metabolism , Sexual Behavior, Animal , Territoriality
3.
Horm Behav ; 53(5): 627-37, 2008 May.
Article in English | MEDLINE | ID: mdl-18313055

ABSTRACT

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.


Subject(s)
Androgens/genetics , Androgens/physiology , Behavior, Animal/physiology , Behavior/physiology , Estrogens/genetics , Estrogens/physiology , Animals , Female , Humans , Male , Receptors, Androgen/genetics , Receptors, Androgen/physiology , Receptors, Estrogen/genetics , Receptors, Estrogen/physiology , Sex Characteristics , Sexual Behavior, Animal/physiology
4.
Learn Mem ; 13(2): 143-9, 2006.
Article in English | MEDLINE | ID: mdl-16585790

ABSTRACT

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.


Subject(s)
Behavior, Animal/physiology , Conditioning, Classical/physiology , Fear/physiology , Genetic Testing , Mice, Mutant Strains , Animals , Environment , Female , Genetics, Behavioral/methods , Male , Memory/physiology , Memory Disorders/genetics , Methylnitrosourea , Mice , Mice, Inbred C57BL , Mutagenesis , Phenotype , Species Specificity
5.
Nat Neurosci ; 8(12): 1660-2, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16261133

ABSTRACT

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.


Subject(s)
Aggression/physiology , Ion Channels/genetics , Olfactory Mucosa/metabolism , Pheromones/physiology , Sexual Behavior, Animal/physiology , Smell/genetics , Animals , Cyclic Nucleotide-Gated Cation Channels , Female , Male , Mice , Mice, Knockout , Neurosecretory Systems/physiology , Olfactory Bulb/physiology , Olfactory Pathways/physiology , Sex Characteristics , Synaptic Transmission/physiology , Vomeronasal Organ/physiology
6.
Neuron ; 36(3): 507-19, 2002 Oct 24.
Article in English | MEDLINE | ID: mdl-12408852

ABSTRACT

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.


Subject(s)
Calcium-Calmodulin-Dependent Protein Kinases/deficiency , Dendrites/enzymology , Hippocampus/enzymology , Hippocampus/growth & development , Long-Term Potentiation/genetics , Memory/physiology , Synaptic Transmission/genetics , Animals , Behavior, Animal/physiology , Calcium-Calmodulin-Dependent Protein Kinase Type 2 , Calcium-Calmodulin-Dependent Protein Kinases/genetics , Chimera , Fear/physiology , Gene Expression Regulation, Enzymologic/genetics , Gene Targeting , Hippocampus/cytology , Maze Learning/physiology , Memory Disorders/enzymology , Memory Disorders/genetics , Memory Disorders/physiopathology , Mice , Mice, Transgenic , Mutation/genetics , Organ Culture Techniques , Phenotype , Protein Isoforms/deficiency , Protein Isoforms/genetics , Synaptic Membranes/genetics , Synaptic Membranes/metabolism
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