Brain estrogens rapidly strengthen auditory encoding and guide song preference in a songbird

Abstract

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. Brain-derived 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.

Fig. 1.

Song preference depends on estrogen production in the left hemisphere. In freely behaving males, preference for BOS (1.0 = 100% BOS preference vs. 0 CON) is eliminated during retrodialysis of the aromatase inhibitor FAD into the left-hemisphere NCM region (**P < 0.007) but not the right. Dashed line represents the species-typical BOS preference ratio (≈75%) (5). Dotted line delineates no preference. Sample sizes in parentheses.

Fig. 2.

Acute fluctuations in local estrogens modulate auditory-evoked activity in NCM. (A) Top: PSTH of 30 presentations of BOS during aCSF (Left) vs. aCSF + estradiol treatment (Right). Middle: Raw multiunit activity (MUA) recording during BOS. Bottom: oscillogram of BOS playback stimulus. (B) Within 30 min estradiol (E2) retrodialysis increases NCM spike rate during zebra finch song playback (BOS, CON, and REV) but not during HET or WN. (C) FAD retrodialysis has no immediate effect, but FAD elevates NCM spike rate during the 30-min washout period for all song stimuli. Spike rates during all treatment periods are standardized to the preceding aCSF period. Sample sizes in parentheses. ^# P < 0.007; *P < 0.05.

Fig. 3.

Estradiol causes acute changes in the occurrence of multiunit bursts. (A) Example of NCM spike trains for both aCSF (Upper) and estradiol (Lower) conditions. Triggered spike plots are depicted below each trace, and two examples of identified burst-periods (black bars) are depicted. Right: ISI distribution plots over the entire 30 min treatment periods from the same experiment are shown for aCSF (Upper) and estradiol (Lower). An increased number of rapid ISI (<5–10 ms) events during estradiol treatment is consistent with a transition from isolated spiking to burst firing. (B) As with NCM spike rate activity, estradiol (E2) increases the number of multiunit bursts during playback of zebra finch songs (BOS, CON, REV) but not during HET or WN stimuli. (C) FAD significantly decreases the number of multiunit bursts (*P < 0.05 for CON1; P > 0.09 for all other post hoc tests for aCSF vs. FAD or Wash vs. aCSF).

Fig. 4.

Local changes in estradiol acutely modulate auditory-evoked activity of single NCM neurons. (A) Upper right: Overlay of 100 random spike waveforms from a single neuron as indentified by PCA. Lower left: PCA plot shows the corresponding unique distribution of spikes (black dots, ellipse = SD) for the same unit (see arrow) during 30 min of playback. (B) Single units show auditory-evoked activity that is enhanced during 30-min estradiol treatment. Inset: BOS oscillogram. Lower: PSTHs for single-unit activity for aCSF and estradiol. (C) Estradiol (E2) increases the number of auditory-evoked single unit bursts in NCM. **P = 0.005, n = 10 units from seven birds. (D) Estradiol also increases the percentage of spikes per burst for single NCM units. *P = 0.036. (E) By contrast, FAD decreases the number of auditory-evoked single unit bursts in NCM. *P = 0.018; n = 7 units from five birds.