ZF Optomodulomics · Dopaminergic modulation of neuronal circuit function in the zebrafish olfactory system

Dopaminergic modulation of neuronal circuit function in the zebrafish olfactory system

Neuromodulatory neurons project to a wide range of target areas and adjust neuronal circuit function by modifying neuronal properties, synaptic transmission and neuronal plasticity. They are further implicated in various cognitive functions such as attention and in neurological disorders like Schizophrenia and addiction. Despite detailed insights into the molecular and cellular actions of neuromodulators, their concerted effects on circuit function are poorly understood, mainly because they have complex combinatorial effects on circuit components and because computational functions of cortical circuits are largely unresolved. Two important neuromodulators involved in many neural disorders are Dopamine (DA) and Acetylcholine (ACh). To uncover fundamental principles and mechanisms by which DA and ACh interact and modulate cortical computations, analyze their effects on odor processing and memory storage in the zebrafish homolog of olfactory cortex (telencephalic area Dp). We created several transgenic Zebrafish lines that enable us to specifically silence or activate DA- or ACh- positive neurons using light (optogenetic methods) or pharmacological agents (pharmacogenetics). In addition, we created transgenic lines expressing genetically encoded reporters of activity in these neurons (Table 1). We verified the cell type specificity of expression pattern (Figure 1 and Figure 2) and further analyzed the distribution and projections of dopaminergic and cholinergic neurons in the forebrain. We designed equipment and protocols for optogenetic stimulation and confirmed that the activity of dopaminergic and cholinergic neurons can be manipulated by light in transgenic fish. Using 2-photon calcium imaging we measured neuronal activity evoked by odor stimulation, optical stimulation of neuromodulatory neurons, or both. Optogenetic stimulation of dopaminergic neurons in the olfactory bulb (OB) (Figure 3) decreased odor responses in Dp, consistent with their presumed inhibitory function (Figure 4). Optical stimulation of dopaminergic and cholinergic fibers in Dp had more complex effects. We are currently capitalizing on the molecular tools created in this project to further analyze dopaminergic and cholinergic effects on odor-evoked activity patterns in Dp and their plasticity in order to obtain further insights into mechanisms underlying distributed sensory processing and memory at the circuit level. In combination with behavioral experiments we will subsequently test whether observed effects are causally involved in olfactory memory. Contact addresses: Rainer Friedrich (rainer.friedrich@fmi.ch) and Anastasios Moressis (anastasios.moressis@fmi.ch)

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