Preceding Inhibition Silences Layer 6 Neurons in Auditory Cortex

Abstract

Summary A canonical feedforward circuit is proposed to underlie sensory cortical responses with balanced excitation and inhibition in layer 4 (L4). However, in another input layer, L6, sensory responses and the underlying synaptic circuits remain largely unclear. Here, cell-attached recordings in rat primary auditory cortex revealed that for the majority of L6 excitatory neurons, tonal stimuli did not drive spike responses, but suppressed spontaneous firings. Whole-cell recordings further revealed that the silencing resulted from tone-evoked strong inhibition arriving earlier than excitation. This pattern of inputs can be attributed to a parallel feedforward circuit with both excitatory and inhibitory inputs disynaptically relayed. In contrast, in the other neurons directly driven by thalamic input, stimuli evoked excitation preceding relatively weak inhibition, resulting in robust spike responses. Thus, the dichotomy of L6 response properties arises from two distinct patterns of excitatory-inhibitory interplay. The parallel circuit module generating preceding inhibition may provide a gating mechanism for conditional corticothalamic feedback.

Spectral breadth and laminar distribution of thalamocortical inputs to A1

“…Previous findings that the deep-layer current sink was sometimes reduced by muscimol may reflect the use of doses Ͼ1 mM (indeed, in our experiments higher doses also could reduce the layer 5/6 response), but overall previous results are generally consistent with a strong thalamocortical contribution (Cruikshank et al 2002;Happel et al 2010;Zhou et al 2010). However, intracellular recordings show that the thalamocortical inputs to layer 5/6 can activate inhibition (Zhou et al 2010), which indicates activation of cortical circuits. Thus the lack of an intracortical contribution in our study may result, in part, from methodology (e.g., level and type of anesthesia), and intracortical activity may be evoked more readily in other conditions, such as during behavior.…”

“…The layer 4 sink had an onset latency of 16.5 Ϯ 0.78 ms (n ϭ 22), which is shorter than that of the layer 2/3 sink (20.5 Ϯ 1.88 ms; paired t-test, P ϭ 0.029) and longer than that of the layer 5/6 sink (13.1 Ϯ 1.57 ms, P Ͻ 0.001). The laminar location, latency, and duration of the layer 5/6 current sink suggest that it results from a collateral of the main thalamocortical projection to layer 4, as noted previously (Cruikshank et al 2002;Romanski and LeDoux 1993;Zhou et al 2010), and the difference in onset latencies over a distance of 300 m implies a conduction velocity of ϳ0.1 m/s, consistent with intracortical (unmyelinated axon) velocities (Salami et al 2003). The onset latency of the layer 2/3 sink is considerably longer than expected for a monosynaptic input, since a similar conduction velocity over the additional 100-m distance from layer 4 should add only ϳ1 ms to the latency (instead of the observed ϳ4 ms).…”

“…Finally, the layer 5/6 current sink is relatively small and brief, and its onset latency is earlier than that of the layer 4 sink. This deep-layer sink likely reflects collateral projections of the main thalamocortical projection to layer 4, as has been proposed in anatomical and physiological studies (Constantinople and Bruno 2013;Cruikshank et al 2002;Zhou et al 2010). Given that the change in onset latency with spectral distance from CF is substantially less in layer 5/6 than in more superficial layers (Fig.…”

“…However, this approach has been questioned on the grounds that muscimol may unintentionally reduce afferent synaptic transmission via nonspecific actions at presynaptic GABA-B receptors (Liu et al 2007;Yamauchi et al 2000). Although such nonspecific actions have not been observed in neocortex, several recent studies have silenced cortical neurons with muscimol paired with a second drug to block possible actions on GABA-B receptors (Happel et al 2010;Hogsden et al 2011;Liu et al 2007;Zhou et al 2010). However, this approach is complicated, in terms of both pharmacology and interpretation (e.g., blockade of presynaptic GABA-B receptors also will affect postsynaptic GABA-B receptors) (see DISCUSSION).…”

Memory formation and retrieval of neuronal silencing in the auditory cortex

“…fear conditioning | operant conditioning | optogenetics | neuronal inhibition | auditory cortex C ortical neurons exhibit spontaneous activity without explicit external stimuli (1-3), which may not only increase, but also be suppressed, by sensory stimuli (4,5). For example, auditory stimuli suppress a subset of auditory cortical neurons in a frequency-dependent manner (5).…”