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Linking genetically defined neurons to behavior through a broadly applicable silencing allele.

ABSTRACT: Tools for suppressing synaptic transmission gain power when able to target highly selective neuron subtypes, thereby sharpening attainable links between neuron type, behavior, and disease; and when able to silence most any neuron subtype, thereby offering broad applicability. Here, we present such a tool, RC::PFtox, that harnesses breadth in scope along with high cell-type selection via combinatorial gene expression to deliver tetanus toxin light chain (tox), an inhibitor of vesicular neurotransmission. When applied in mice, we observed cell-type-specific disruption of vesicle exocytosis accompanied by loss of excitatory postsynaptic currents and commensurately perturbed behaviors. Among various test populations, we applied RC::PFtox to silence serotonergic neurons, en masse or a subset defined combinatorially. Of the behavioral phenotypes observed upon en masse serotonergic silencing, only one mapped to the combinatorially defined subset. These findings provide evidence for separability by genetic lineage of serotonin-modulated behaviors; collectively, these findings demonstrate broad utility of RC::PFtox for dissecting neuron functions.

SUBMITTER: Kim JC

PROVIDER: S-EPMC2814245 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Linking genetically defined neurons to behavior through a broadly applicable silencing allele.

Kim Jun Chul JC Cook Melloni N MN Carey Megan R MR Shen Chung C Regehr Wade G WG Dymecki Susan M SM

Neuron 20090801 3

Tools for suppressing synaptic transmission gain power when able to target highly selective neuron subtypes, thereby sharpening attainable links between neuron type, behavior, and disease; and when able to silence most any neuron subtype, thereby offering broad applicability. Here, we present such a tool, RC::PFtox, that harnesses breadth in scope along with high cell-type selection via combinatorial gene expression to deliver tetanus toxin light chain (tox), an inhibitor of vesicular neurotrans ...[more]

PMID: 19679071

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Project description:Dopamine (DA) neurons of the ventral tegmental area (VTA) continue to gain attention as far more heterogeneous than previously realized. Within the medial aspect of the VTA, the unexpected presence of TrpV1 mRNA has been identified. TrpV1 encodes the Transient Receptor Potential cation channel subfamily V member 1, TRPV1, also known as the capsaicin receptor, well recognized for its role in heat and pain processing by peripheral neurons. In contrast, the brain distribution of TrpV1 has been debated. Here, we hypothesized that the TrpV1+ identity defines a distinct subpopulation of VTA DA neurons. To explore these brain TrpV1+ neurons, histological analyses and Cre-driven mouse genetics were employed. TrpV1 mRNA was most strongly detected at the perinatal stage forming a band of scattered neurons throughout the medial VTA, reaching into the posterior hypothalamus. Within the VTA, the majority of TrpV1 co-localized with both Tyrosine hydroxylase (Th) and Vesicular monoamine transporter 2 (Vmat2), confirming a DA phenotype. However, TrpV1 also co-localized substantially with Vesicular glutamate transporter 2 (Vglut2), representing the capacity for glutamate (GLU) release. These TrpV1+/Th+/Vglut2+/Vmat2+ neurons thus constitute a molecularly and anatomically distinct subpopulation of DA-GLU co-releasing neurons. To assess behavioral impact, a TrpV1 Cre -driven strategy targeting the Vmat2 gene in mice was implemented. This manipulation was sufficient to alter psychomotor behavior induced by amphetamine. The acute effect of the drug was accentuated above control levels, suggesting super-sensitivity in the drug-na ve state resembling a "pre-sensitized" phenotype. However, no progressive increase with repeated injections was observed. This study identifies a distinct TrpV1+ VTA subpopulation as a critical modulatory component in responsiveness to amphetamine. Moreover, expression of the gene encoding TRPV1 in selected VTA neurons opens up for new possibilities in pharmacological intervention of this heterogeneous, but clinically important, brain area.

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Linking genetically defined neurons to behavior through a broadly applicable silencing allele.

Publications

Linking genetically defined neurons to behavior through a broadly applicable silencing allele.

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