Genetic and Optogenetic Models to Dissect the Role of the Serotonin 1B Receptor

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DESCRIPTION (provided by applicant): Aggression and impulsivity are two understudied aspects of behavior that are significant symptoms in a number of psychiatric disorders. The serotonin 1B receptor (5-HT1B R) has been implicated in aggressive and impulsive behavior using pharmacology, constitutive knock-out mouse models, and human gene polymorphism association studies. Given evidence of serotonergic modulation of brain development, it is likely that 5-HT1B R plays a developmental role in establishing circuits underlying aggressive and impulsive behavior. 5-HT1B R is a GPCR that inhibits neurotransmitter release in axon terminals of serotonergic and non-serotonergic neurons localized broadly in the basal ganglia, hippocampus, thalamus, cerebellum and raphe. Thus, an inducible and tissue specific strategy is necessary to delineate the sensitive period and neural circuits through which 5-HT1B Rs regulate aggression and impulsivity. We have therefore generated a mouse line that permits temporal and spatial regulation of 5-HT1B R. A tetracycline operator (tetO) has been inserted between the promoter and coding region of the 5-HT1B R (tetO1B). Receptor binding and in situ hybridization reveals that these tetO1B mice have normal basal 5-HT1B R expression in the brain compared to 129 WT mice. Crossing tetO1B mice to transgenic mice expressing the tetracycline-dependent transcriptional silencer (tTS) under the control of ¿-Actin (ubiquitous), CaMKII (forebrain-specific) or Pet (raphe-specific) promoters yields mouse lines with tissue specific and inducible knock-down of 5-HT1B R. Initial characterization with autoradiography and in situ hybridization reveals promoter-specific 5-HT1B R expression patterns that can be modulated with doxycycline administration. Preliminary behavioral assays using tetO1B:: ¿-Actin-tTS+ mice reveal a similar behavioral phenotype to the constitutive knock-out mouse-i.e., significantly increased impulsive aggression. Therefore, we have the tools to manipulate the expression of 5-HT1B R spatially and temporally and examine the resulting impact on aggressive and impulsive behaviors. Follow-up studies using optogenetics will address the circuit level mechanisms by determining which brain regions in the aggression and impulsivity circuitry in adulthood may have been altered by the intervention during the critical period. The hypothesis is that a lack of 5HT1B Rs during a critical period of development results in an overactive 'aggression circuit', and so by inhibiting these overactive brain regions, a normal phenotype can be rescued. This is possible using the light-sensitive inhibitory Cl- pump, halorhodopsin, introduced through viral vector injection into target brain regions, with subsequent activation by yellow light administered via fiber optic implant. Overall, understanding how 5-HT1B R mediates the neural circuits underlying aggression and impulsivity will have implications for the treatments of several neuropsychiatric disorders, including addiction, attention-deficit hyperactivity disorde and bipolar disorder, and suicidal depression.