Potentiation of cholinergic and corticofugal inputs to the lateral amygdala in threat learning.

The amygdala, cholinergic basal forebrain, and higher-order auditory cortex (HO-AC) regulate brain-wide plasticity underlying auditory threat learning. Here, we perform multi-regional extracellular recordings and optical measurements of acetylcholine (ACh) release to characterize the development of discriminative plasticity within and between these brain regions as mice acquire and recall auditory threat memories. Spiking responses are potentiated for sounds paired with shock (CS+) in the lateral amygdala (LA) and optogenetically identified corticoamygdalar projection neurons, although not in neighboring HO-AC units. Spike- or optogenetically triggered local field potentials reveal enhanced corticofugal-but not corticopetal-functional coupling between HO-AC and LA during threat memory recall that is correlated with pupil-indexed memory strength. We also note robust sound-evoked ACh release that rapidly potentiates for the CS+ in LA but habituates across sessions in HO-AC. These findings highlight a distributed and cooperative plasticity in LA inputs as mice learn to reappraise neutral stimuli as possible threats.

New revelations from the zone of uncertainty.

In this issue of Neuron, Schroeder et al.1 provide the first functional account of inhibitory signaling from the zona incerta to neocortex in behaving animals. Incertocortical afferents exhibit bidirectional plasticity during threat learning, highlighting a distinct top-down signaling regime.

Potentiated cholinergic and corticofugal inputs support reorganized sensory processing in the basolateral amygdala during auditory threat acquisition and retrieval.

Reappraising neutral stimuli as environmental threats reflects rapid and discriminative changes in sensory processing within the basolateral amygdala (BLA). To understand how BLA inputs are also reorganized during discriminative threat learning, we performed multi-regional measurements of acetylcholine (ACh) release, single unit spiking, and functional coupling in the mouse BLA and higher-order auditory cortex (HO-AC). During threat memory recall, sounds paired with shock (CS+) elicited relatively higher firing rates in BLA units and optogenetically targeted corticoamygdalar (CAmy) units, though not in neighboring HO-AC units. Functional coupling was potentiated for descending CAmy projections prior to and during CS+ threat memory recall but ascending amygdalocortical coupling was unchanged. During threat acquisition, sound-evoked ACh release was selectively enhanced for the CS+ in BLA but not HO-AC. These findings suggest that phasic cholinergic inputs facilitate discriminative plasticity in the BLA during threat acquisition that is subsequently reinforced through potentiated auditory corticofugal inputs during memory recall.

Behavioral Approaches to Study Top-Down Influences on Active Listening.

The massive network of descending corticofugal projections has been long-recognized by anatomists, but their functional contributions to sound processing and auditory-guided behaviors remain a mystery. Most efforts to characterize the auditory corticofugal system have been inductive; wherein function is inferred from a few studies employing a wide range of methods to manipulate varying limbs of the descending system in a variety of species and preparations. An alternative approach, which we focus on here, is to first establish auditory-guided behaviors that reflect the contribution of top-down influences on auditory perception. To this end, we postulate that auditory corticofugal systems may contribute to active listening behaviors in which the timing of bottom-up sound cues can be predicted from top-down signals arising from cross-modal cues, temporal integration, or self-initiated movements. Here, we describe a behavioral framework for investigating how auditory perceptual performance is enhanced when subjects can anticipate the timing of upcoming target sounds. Our first paradigm, studied both in human subjects and mice, reports species-specific differences in visually cued expectation of sound onset in a signal-in-noise detection task. A second paradigm performed in mice reveals the benefits of temporal regularity as a perceptual grouping cue when detecting repeating target tones in complex background noise. A final behavioral approach demonstrates significant improvements in frequency discrimination threshold and perceptual sensitivity when auditory targets are presented at a predictable temporal interval following motor self-initiation of the trial. Collectively, these three behavioral approaches identify paradigms to study top-down influences on sound perception that are amenable to head-fixed preparations in genetically tractable animals, where it is possible to monitor and manipulate particular nodes of the descending auditory pathway with unparalleled precision.

Inverted central auditory hierarchies for encoding local intervals and global temporal patterns.

In sensory systems, representational features of increasing complexity emerge at successive stages of processing. In the mammalian auditory pathway, the clearest change from brainstem to cortex is defined by what is lost, not by what is gained, in that high-fidelity temporal coding becomes increasingly restricted to slower acoustic modulation rates.1,2 Here, we explore the idea that sluggish temporal processing is more than just an inability for fast processing, but instead reflects an emergent specialization for encoding sound features that unfold on very slow timescales.3,4 We performed simultaneous single unit ensemble recordings from three hierarchical stages of auditory processing in awake mice - the inferior colliculus (IC), medial geniculate body of the thalamus (MGB) and primary auditory cortex (A1). As expected, temporal coding of brief local intervals (0.001 - 0.1 s) separating consecutive noise bursts was robust in the IC and declined across MGB and A1. By contrast, slowly developing (∼1 s period) global rhythmic patterns of inter-burst interval sequences strongly modulated A1 spiking, were weakly captured by MGB neurons, and not at all by IC neurons. Shifts in stimulus regularity were not represented by changes in A1 spike rates, but rather in how the spikes were arranged in time. These findings show that low-level auditory neurons with fast timescales encode isolated sound features but not the longer gestalt, while the extended timescales in higher-level areas can facilitate sensitivity to slower contextual changes in the sensory environment.

Publisher Correction: Sensory overamplification in layer 5 auditory corticofugal projection neurons following cochlear nerve synaptic damage.

In the originally published version of this Article, refs. 54 to 63 were incorrectly cited in the first sentence of the fifth paragraph of the Discussion section. This has now been corrected in both the PDF and HTML versions of the Article.

Sensory overamplification in layer 5 auditory corticofugal projection neurons following cochlear nerve synaptic damage.

Layer 5 (L5) cortical projection neurons innervate far-ranging brain areas to coordinate integrative sensory processing and adaptive behaviors. Here, we characterize a plasticity in L5 auditory cortex (ACtx) neurons that innervate the inferior colliculus (IC), thalamus, lateral amygdala and striatum. We track daily changes in sound processing using chronic widefield calcium imaging of L5 axon terminals on the dorsal cap of the IC in awake, adult mice. Sound level growth functions at the level of the auditory nerve and corticocollicular axon terminals are both strongly depressed hours after noise-induced damage of cochlear afferent synapses. Corticocollicular response gain rebounded above baseline levels by the following day and remained elevated for several weeks despite a persistent reduction in auditory nerve input. Sustained potentiation of excitatory ACtx projection neurons that innervate multiple limbic and subcortical auditory centers may underlie hyperexcitability and aberrant functional coupling of distributed brain networks in tinnitus and hyperacusis.