Presynaptic inhibition reduces chemical synaptic transmission in the central nervous system between pairs of neurons, but its role(s) in shaping the multisynaptic interactions underlying neural network activity are not well studied. We therefore used the crustacean stomatogastric nervous system to study how presynaptic inhibition of the identified projection neuron, modulatory commissural neuron 1 (MCN1), influences the MCN1 synaptic effects on the gastric mill neural network. Tonic MCN1 discharge excites gastric mill network neurons and activates the gastric mill rhythm. One network neuron, the lateral gastric (LG) neuron, presynaptically inhibits MCN1 and is electrically coupled to its terminals. We show here that this presynaptic inhibition selectively reduces or eliminates transmitter-mediated excitation from MCN1 without reducing its electrically mediated excitatory effects, thereby switching the network neurons excited by MCN1. By switching the type of synaptic output from MCN1 and, hence, the activated network neurons, this presynaptic inhibition is pivotal to motor pattern generation.

Higher cognitive function depends on accurate detection and processing of subtle features of sensory stimuli. Such precise computations require neural circuits to be modulated over rapid timescales, yet this modulation is poorly understood. Brainderived steroids (neurosteroids) can act as fast signaling molecules in the vertebrate central nervous system and could therefore modulate sensory processing and guide behavior, but there is no empirical evidence for this possibility. Here we report that acute inhibition of estrogen production within a cortical-like region involved in complex auditory processing disrupts a songbird's ability to behaviorally respond to song stimuli. Identical manipulation of local estrogen levels rapidly changes burst firing of single auditory neurons. This acute estrogen-mediated modulation targets song and not other auditory stimuli, possibly enabling discrimination among species-specific signals. Our results demonstrate a crucial role for neuroestrogen synthesis among vertebrates for enhanced sensory encoding. Cognitive impairments associated with estrogen depletion, including verbal memory loss in humans, may therefore stem from compromised moment-by-moment estrogen actions in higher-order cortical circuits.I n vertebrates, steroid hormones can rapidly influence the activity of neurons and neural circuits (1-3), although the functional consequences for higher processing are unclear. The exquisite recognition of species-typical vocalizations (4, 5) and abundant production of neuroestrogens (6, 7) are both especially prominent in songbirds. A cortical-like auditory region (the caudomedial nidopallium, or NCM) of songbirds is a critical locus for song learning as well as auditory processing and song recognition (8-11). NCM exhibits rich expression of the estrogen-synthetic enzyme aromatase in both cell bodies and synaptic terminals (6, 12), and neuroestrogen levels within NCM fluctuate rapidly (<30 min) and independent of peripheral sex-steroid levels during social interactions, song playback, and after neurotransmitter activation (13). In songbirds, therefore, rapid changes in the local production of NCM neuroestrogens could in turn rapidly affect processing of complex auditory stimuli, such as song.Here, we test this hypothesis in male Australian zebra finches (Taeniopygia guttata). Our recent optimization of in vivo microdialysis in this species has enabled the measurement and manipulation of local estrogen production within discrete brain regions in awake, behaving males (13). We have further established that local estrogen levels are dependent on the activity of the enzyme aromatase within NCM, because retrodialysis (reverse delivery using microdialysis) of the aromatase inhibitor fadrozole (FAD) into NCM transiently suppresses local estradiol levels (13). ResultsIn Vivo Retrodialysis and Behavior. Adult zebra finches express a robust behavioral preference for acoustic playback of their tutor's song or bird's own song (BOS) compared with conspecific male song (CON) (4, 5, 8), and be...