Estrogens rapidly shape synaptic and intrinsic properties to regulate the temporal precision of songbird auditory neurons.

Sensory neurons parse millisecond-variant sound streams like birdsong and speech with exquisite precision. The auditory pallial cortex of vocal learners like humans and songbirds contains an unconventional neuromodulatory system: neuronal expression of the estrogen synthesis enzyme aromatase. Local forebrain neuroestrogens fluctuate when songbirds hear a song, and subsequently modulate bursting, gain, and temporal coding properties of auditory neurons. However, the way neuroestrogens shape intrinsic and synaptic properties of sensory neurons remains unknown. Here, using a combination of whole-cell patch clamp electrophysiology and calcium imaging, we investigate estrogenic neuromodulation of auditory neurons in a region resembling mammalian auditory association cortex. We found that estradiol rapidly enhances the temporal precision of neuronal firing via a membrane-bound G-protein coupled receptor and that estradiol rapidly suppresses inhibitory synaptic currents while sparing excitation. Notably, the rapid suppression of intrinsic excitability by estradiol was predicted by membrane input resistance and was observed in both males and females. These findings were corroborated by analysis of in vivo electrophysiology recordings, in which local estrogen synthesis blockade caused acute disruption of the temporal correlation of song-evoked firing patterns. Therefore, on a modulatory timescale, neuroestrogens alter intrinsic cellular properties and inhibitory neurotransmitter release to regulate the temporal precision of higher-order sensory neurons.

Differential Effects of Dorsal and Ventral Medial Prefrontal Cortex Inactivation during Natural Reward Seeking, Extinction, and Cue-Induced Reinstatement.

Rodent dorsal medial prefrontal cortex (mPFC), typically prelimbic cortex, is often described as promoting actions such as reward seeking, whereas ventral mPFC, typically infralimbic cortex, is thought to promote response inhibition. However, both dorsal and ventral mPFC are necessary for both expression and suppression of different behaviors, and each region may contribute to different functions depending on the specifics of the behavior tested. To better understand the roles of dorsal and ventral mPFC in motivated behavior we pharmacologically inactivated each area during operant fixed ratio 1 (FR1) seeking for a natural reward (sucrose), extinction, cue-induced reinstatement, and progressive ratio (PR) sucrose seeking in male Long-Evans rats. Bilateral inactivation of dorsal mPFC, but not ventral mPFC increased reward seeking during FR1. Inactivation of both dorsal and ventral mPFC decreased seeking during extinction. Bilateral inactivation of ventral mPFC, but not dorsal mPFC decreased reward seeking during cue-induced reinstatement. No effect of inactivation was found during PR. Our data contrast sharply with observations seen during drug seeking and fear conditioning, indicating that previously established roles of dorsal mPFC = going versus ventral mPFC = stopping are not applicable to all motivated behaviors and/or outcomes. Our results indicate that dichotomous functions of dorsal versus ventral mPFC, if they exist, may align better with other models, or may require the development of a new framework in which these multifaceted brain areas play different roles in action control depending on the behavioral context in which they are engaged.

Clustered organization and region-specific identities of estrogen-producing neurons in the forebrain of Zebra Finches (Taeniopygia guttata).

A fast, neuromodulatory role for estrogen signaling has been reported in many regions of the vertebrate brain. Regional differences in the cellular distribution of aromatase (estrogen synthase) in several species suggest that mechanisms for neuroestrogen signaling differ between and even within brain regions. A more comprehensive understanding of neuroestrogen signaling depends on characterizing the cellular identities of neurons that express aromatase. Calcium-binding proteins such as parvalbumin and calbindin are molecular markers for interneuron subtypes, and are co-expressed with aromatase in human temporal cortex. Songbirds like the zebra finch have become important models to understand the brain synthesis of steroids like estrogens and the implications for neurobiology and behavior. Here, we investigated the regional differences in cytoarchitecture and cellular identities of aromatase-expressing neurons in the auditory and sensorimotor forebrain of zebra finches. Aromatase was co-expressed with parvalbumin in the caudomedial nidopallium (NCM) and HVC shelf (proper name) but not in the caudolateral nidopallium (NCL) or hippocampus. By contrast, calbindin was not co-expressed with aromatase in any region investigated. Notably, aromatase-expressing neurons were found in dense somato-somatic clusters, suggesting a coordinated release of local neuroestrogens from clustered neurons. Aromatase clusters were also more abundant and tightly packed in the NCM of males as compared to females. Overall, this study provides new insights into neuroestrogen regulation at the network level, and extends previous findings from human cortex by identifying a subset of aromatase neurons as putative inhibitory interneurons.