Presynaptic inhibition of dopamine neurons controls optimistic bias

Regulation of reward signaling in the brain is critical for appropriate judgement of the environment and self. In Drosophila, the protocerebral anterior medial (PAM) cluster dopamine neurons mediate reward signals. Here, we show that localized inhibitory input to the presynaptic terminals of the PAM neurons titrates olfactory reward memory and controls memory specificity. The inhibitory regulation was mediated by metabotropic gamma-aminobutyric acid (GABA) receptors clustered in presynaptic microdomain of the PAM boutons. Cell type-specific silencing the GABA receptors enhanced memory by augmenting internal reward signals. Strikingly, the disruption of GABA signaling reduced memory specificity to the rewarded odor by changing local odor representations in the presynaptic terminals of the PAM neurons. The inhibitory microcircuit of the dopamine neurons is thus crucial for both reward values and memory specificity. Maladaptive presynaptic regulation causes optimistic cognitive bias.

The role of agonistic/antagonistic activity in the development of psychotropic effects of antipsychotics

The development of psychotic symptoms is traditionally linked to the increase of the functional activity of endogenous dopaminergic system. Antipsychotic effect of existing medications is associated with direct blockade of postsynaptic dopamine receptors. However, direct antagonistic activity is «alien» to physiological mechanisms of neurotransmission modulation, and presynaptic autoreceptor blockade mау produce a reverse (agonistic) effect, enhancing neurotransmitter release. On the other hand, anti-dopamine effect can be achieved by indirect antagonistic activity—by presynaptic dopamine depletion, which is consistent with the natural, physiological mechanisms of reducing neurotransmission. It can be assumed that modulation of presynaptic regulation is one of the promising directions for the development of antipsychotic drugs of future generations.

Presynaptic MAST Kinase Controls Bidirectional Post-Synaptic Responses to Convey Stimulus Valence in C. elegans

Presynaptic plasticity is known to modulate the strength of synaptic transmission. However, it remains unknown whether regulation in presynaptic neurons alters the directionality –positive or negative-of postsynaptic responses. We report here that the C. elegans homologs of MAST kinase, Stomatin and Diacylglycerol kinase act in a thermosensory neuron to elicit in its postsynaptic neuron an excitatory or inhibitory response that correlates with the valence of thermal stimuli. By monitoring neural activity of the valence-coding interneuron in freely behaving animals, we show that the alteration between excitatory and inhibitory responses of the interneuron is mediated by controlling the balance of two opposing signals released from the presynaptic neuron. These alternative transmissions further generate opposing behavioral outputs necessary for the navigation on thermal gradients. Our findings reveal the previously unrecognized capability of presynaptic regulation to evoke bidirectional postsynaptic responses and suggest a molecular mechanism of determining stimulus valence.