Corticofugal projections to evolutionarily ancient, subcortical structures are ubiquitous across mammalian sensory systems. These ‘descending’ pathways enable the neocortex to control ascending sensory representations in a predictive or feedback manner, but the underlying cellular mechanisms are poorly understood. Here, we combine optogenetic approaches with in vivo and in vitro patch-clamp electrophysiology to study the projection from mouse auditory cortex to the inferior colliculus (IC), a major descending auditory pathway that controls IC neuron feature selectivity, plasticity, and auditory perceptual learning. Although individual auditory cortico-collicular synapses were generally weak, IC neurons often integrated inputs from multiple corticofugal axons that generated reliable, tonic depolarizations even during prolonged presynaptic activity. Latency measurements in vivo showed that descending signals reach the IC within 30 ms of sound onset, which in IC neurons corresponded to the peak of synaptic depolarizations evoked by short sounds. Activating ascending and descending pathways at latencies expected in vivo caused a NMDA receptor-dependent, supralinear excitatory postsynaptic potential summation, indicating that descending signals can nonlinearly amplify IC neurons’ moment-to-moment acoustic responses. Our results shed light upon the synaptic bases of descending sensory control and imply that heterosynaptic cooperativity contributes to the auditory cortico-collicular pathway’s role in plasticity and perceptual learning.
Layer 5 pyramidal neurons of sensory cortices project corticofugal axons to myriad of sub-cortical targets, thereby broadcasting high-level signals important for perception and learning. Recent studies suggest dendritic Ca2+ spikes as key biophysical mechanisms supporting corticofugal neuron function: These long-lasting events drive burst firing, thereby initiating uniquely powerful signals to modulate sub-cortical representations and trigger learning-related plasticity. However, the behavioral relevance of corticofugal dendritic spikes is poorly understood. We shed light on this issue using 2-photon Ca2+ imaging of auditory corticofugal dendrites as mice engage in a sound-discrimination task. Unexpectedly, only a minority of dendritic spikes were triggered by sound. Rather, task-related dendritic activity mostly occurred following sound termination and reflected instrumental actions, irrespective of reward consumption. Temporally selective silencing of this motor-related activity impaired auditory discrimination learning. Thus, corticofugal systems contribution to learning and plasticity may be largely motor, rather than sensory in nature.
The inferior colliculus (IC) is a midbrain hub critical for perceiving complex, time-varying sounds such as speech. In addition to processing ascending inputs from most auditory brainstem nuclei, the IC receives descending inputs from auditory cortex that control IC neuron feature selectivity, plasticity, and certain forms of perceptual learning. Although these corticofugal synapses primarily release the excitatory transmitter glutamate, many physiology studies show that auditory cortical activity has a net inhibitory effect on IC neuron spiking. Perplexingly, anatomy studies indicate that corticofugal axons primarily target glutamatergic IC neurons while only sparsely innervating IC GABA neurons, thereby suggesting that corticofugal inhibition of the IC occurs largely independently of feedforward activation of local GABA neurons. We shed light on this paradox using in vitro electrophysiology and optogenetics in acute IC slices from fluorescent reporter mice. We find that corticofugal synaptic strength is indeed stronger onto IC glutamate compared to GABA neurons. Nevertheless, two mechanisms enable reliable corticofugal activation of local GABA neurons. 1) Many IC GABA neurons fire tonically at rest, such that sparse and weak excitation suffices to significantly increase their spike rates. 2) Corticofugal activity triggers barrages of large amplitude, polysynaptic EPSPs in IC GABA neurons, owing to a dense intra-collicular connectivity from local axon collaterals of IC glutamate neurons. Consequently, repetitive activity in corticofugal fibers drives spikes in IC GABA neurons and generates substantial recurrent inhibition. Thus, descending signals trigger intra-collicular inhibition despite apparent constraints of monosynaptic connectivity between auditory cortex and IC GABA neurons.
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