Dopamine-modulated recurrent corticoefferent feedback in primary sensory cortex promotes detection of behaviorally relevant stimuli

Abstract

Dopaminergic neurotransmission in primary auditory cortex (AI) has been shown to be involved in learning and memory functions. Moreover, dopaminergic projections and D1/D5 receptor distributions display a layer-dependent organization, suggesting specific functions in the cortical circuitry. However, the circuit effects of dopaminergic neurotransmission in sensory cortex and their possible roles in perception, learning, and memory are largely unknown. Here, we investigated layer-specific circuit effects of dopaminergic neuromodulation using current source density (CSD) analysis in AI of Mongolian gerbils. Pharmacological stimulation of D1/D5 receptors increased auditory-evoked synaptic currents in infragranular layers, prolonging local thalamocortical input via positive feedback between infragranular output and granular input. Subsequently, dopamine promoted sustained cortical activation by prolonged recruitment of long-range corticocortical networks. A detailed circuit analysis combining layer-specific intracortical microstimulation (ICMS), CSD analysis, and pharmacological cortical silencing revealed that cross-laminar feedback enhanced by dopamine relied on a positive, fast-acting recurrent corticoefferent loop, most likely relayed via local thalamic circuits. Behavioral signal detection analysis further showed that activation of corticoefferent output by infragranular ICMS, which mimicked auditory activation under dopaminergic influence, was most effective in eliciting a behaviorally detectable signal. Our results show that D1/D5-mediated dopaminergic modulation in sensory cortex regulates positive recurrent corticoefferent feedback, which enhances states of high, persistent activity in sensory cortex evoked by behaviorally relevant stimuli. In boosting horizontal network interactions, this potentially promotes the readout of task-related information from cortical synapses and improves behavioral stimulus detection.

Keywords: auditory cortex; behavior; corticoefferent recurrence; dopamine; perception.

Figure 1.

Schematic overview of the experimental design. A, Experimental setting for electrophysiological recordings and layer-specific modulation of activity using (1) pharmacological activation of D₁/D₅ receptors predominantly located within infragranular, corticoefferent layers (green circles) or (2) intracortical microstimulation at different cortical depths (red circles). B, Laminar LFP recordings were used for CSD analysis to determine spatiotemporal patterns of synaptic current flow (Happel et al., 2010) required for a layer-specific interpretation of electrically and auditory evoked activity in relation to the underlying local cortical microcircuitry at the recording site. Stimulation and recording electrodes were positioned along the rostrocaudal axis of AI to target different tonotopic regions (Budinger et al., 2006). C, Location of the stimulation channels across the cortical layers indicated by Prussian blue staining, as used for electrophysiology and behavior (see Materials and Methods). Indicated are the electrode tracks of the stimulation electrode. Inset at bottom shows a cross section of the vertically aligned lateral stimulation array. Scale bar, 200 μm. D, Illustration of the behavioral paradigm: Go/NoGo task for investigating behavioral detection of ICMS in a shuttlebox, in order for establish relationships between perception and the recruitment of different corticocortical and recurrent corticoefferent pathways through layer-specific ICMS.

Figure 2.

Interaction between thalamocortical input and corticoefferent output layers induced by dopaminergic stimulation. A, Pure-tone evoked CSD profile in response to best-frequency stimulation (2 kHz in the example shown) revealed a canonical polysynaptic cascade of laminar cortical processing in primary auditory cortex (left). Cortical activation commences in granular input layers and entails extragranular activations (G sink followed by subsequent extragranular IG and SG sinks). Application of D₁/D₅ agonist SKF38393 increased short-latency, early infragranular sink activation that correlated with stronger synaptic current flow in granular layers (see D) within a time window of ∼25 ms after tone-evoked onset (right). Cortical layers indicated here and the following CSD plots were derived from histological analysis and represent mean relations in gerbil AI (Happel et al., 2010). B, Laminar extent of individual SG, G, and IG sinks in untreated cortex and after application of D₁/D₅ agonist SKF38393 and antagonist SCH23390, demonstrating recording track stability throughout and across the experiments. Channels with the shortest onset latencies chosen for averaging (see Materials and Methods) were not significantly different across conditions (black boxes, #; paired-sample Student's t test). The full spatial extent of corresponding sink components including channels with longer onset latencies not used for averaging (colored rectangles; dashed lines, SEM) significantly increased with the application of SKF38939 only for IG sink. This effect was reversed after the application of the antagonist (*paired-sample Student's t test; see Results). C, Cumulative mean peak amplitudes from onset to peak within different layers before and after SKF38393 application. D, Duration of initial and late phases of the AVREC (>3 SDs above baseline) were both prolonged by the application of SKF38393. E, AVREC mean integral of initial (top) and late (bottom) phase (pale color), and by unbalanced current flow during each phase (dark color) originating from horizontal corticocortical input obtained from weighting the AVREC by the mean relative residuals (Happel et al., 2010).

Figure 3.

Temporal relation of granular and infragranular sink activity by correlation analysis. A, Typical example of granular (blue) and infragranular (red) CSD signals from a single animal in response to acoustic stimulation before (top) and after (bottom) administration of SKF38393. CSD signals were averaged across the granular and infragranular channels showing the main sink components, respectively. Peak latencies are marked by dashed lines. B, Mean peak latencies of the granular and infragranular sink before (left) and after application of SKF38393 (right). SKF38393 exclusively increased the peak latency of the initial granular sink (#; for rmANOVA; see Table 1, 1.3). C, Normalized cross-correlation between granular and infragranular layers after the first sink onset as a function of the relative lag of 25 ms analysis windows. SKF38393 significantly enhanced correlation most prominently around granular lags of 3–14 ms, and shifted the peak of the correlogram from 2.5 to 5.5 ms. For statistical results, see text.

Figure 4.

Dissociation of local intracortical polysynaptic and thalamocortical monosynaptic inputs during layer-specific ICMS. A, Left, In proximal distance to the stimulation site (300 μm), granular (III/IV) and infragranular (V/VI) ICMS evoked CSD profiles with a canonical cross-laminar pattern of activation comparable to auditory stimulation (G sink followed by subsequent extragranular IG and SG sinks). Supragranular ICMS (I/II) did not evoke cross-laminar interactions. Right, During cortical silencing, stimulation of both infragranular and granular layers mainly activated input layer IV (CSD amplitude reduction to 10–30% of original values; compare with color bar scaling; Fig. 5A). During supragranular stimulation, evoked activity was completely abolished by silencing. B, Long-distance polysynaptic activations during distal ICMS led to a similar cascade of cross-laminar activations at distal cortical sites regardless of stimulation depth. Nevertheless, granular ICMS evoked the strongest network activations compared with supragranular and infragranular ICMS. Right, Cortical silencing revealed that distal activations of local microcircuits were transmitted almost exclusively via polysynaptic horizontal intracortical pathways, most effectively when stimulating cortical input layers. Stimulation electrodes (red lines) and stimulation depth (yellow square) are schematically indicated on the left.

Figure 5.

Comparison of laminar CSD responses. Mean (±SEM) peak amplitudes and onset latencies of SG, G, and IG sinks evoked by proximal stimulation (prox. stim.; A) or distal stimulation (dist. stim.; B) in SG (I/II), G (III/IV), or IG (V/VI) layers are shown before (blue) and after (gray) cortical silencing across animals. A, Proximal stimulation elicited the strongest amplitudes in stimulated layers and a decreased activation of granular layers during granular and infragranular ICMS after cortical silencing. B, Mean peak amplitudes during distal stimulation showed similar symmetric relative amplitude and latency ratios (see insets depicting the corresponding LSIs; see C) regardless of stimulation depth. Cortical silencing abolished all distal network activations. C, Quantification of relative cross-laminar activation patterns by an LSI computed by LSI = (SG/G)/(IG/G) for estimating the extragranular activations in relation to the activation of the granular layers independent from the absolute amplitude values. Top, The LSI revealed that the relative activation strength between layers depended only on the stimulation depth proximal to the stimulation site, with a gradual shift of activation toward the stimulated layers (LSI I/II = 3.10 ± 0.42; LSI III/IV = 1.19 ± 0.08; LSI V/VI = 3.87 ± 0.59). At distal sites laminar activation was independent from stimulation depth (LSI I/II = 2.01 ± 0.77; LSI III/IV = 2.20 ± 0.54; LSI V/VI = 1.72 ± 0.34). See Table 1, 1.8, for statistical results. Auditory evoked cross-laminar profiles in untreated cortex (bottom) were comparable to the profiles after distal ICMS and showed stronger supragranular compared with infragranular responses (1.76 ± 0.16), while dopaminergic neurotransmission strongly shifted cortical activation toward deeper corticoefferent layers (LSI = 0.27 ± 0.03; paired-sample Student's t test, p < 0.001).

Figure 6.

Lateral extent of recurrent corticoefferent feedback driven by infragranular ICMS. A, Example of CSD profiles evoked by infragranular ICMS at sites up to a lateral distances of 1200 μm to the recording site (CSD profiles at 1500 μm distance are not shown, because they were identical to those at 1200 μm). However, persisting granular sinks after cortical silencing were found only within a spatial range of up to 600 μm around the stimulation site. Notably, the strong infragranular sink in untreated cortex extends over a similar spatial range of 300–600 μm. B, Normalized mean peak amplitude averaged across animals as a function of distance showed a larger horizontal trans-synaptic spread of activity evoked by ICMS in granular compared with infragranular layers. After cortical silencing, the lateral spread of the granular sink was highly similar to the lateral spread of the untreated infragranular sink.

Figure 7.

Behavioral detection of layer-specific ICMS. A, Monopolar (left) and bipolar (right) electrical stimulus configurations applied to each individual animal. Black arrows indicate the preferred orientation of fiber activation in the different bipolar configurations (BP-ICMS; IC, IG cathodic; IA, IG anodic; SC, SG cathodic; SA, SG anodic). See also graphic illustration on the right (Ranck, 1975). B, During initial avoidance learning, a sequence of monopolar layer-specific pulse trains (80 μA, 300 ms) served as the conditioned stimulus. Stimulation depth varied randomly across trials of a session. The development of detection performance over training sessions was quantified separately for each stimulation depth by mean d′ values (±SEM) across all animals (n = 10). C, Psychometric analysis of mean d′ values (±SEM) across animals as a function of stimulation amplitude (5–100 μA) showed an earlier increase of detection sensitivity with infragranular ICMS (35.60 ± 2.88 μA) compared with ICMS in other layers. See also E. D, The mean d′ value (±SEM) of BP-ICMS configurations was lowest with the preferential activation of infragranular fibers in a corticoefferent direction (IC; 20.50 ± 5.60 μA). See also A. E, Quantitative comparison of stimulation amplitudes (in microamperes) at the threshold criterion of d′ = 1.0 determined individually in each animals, and for each monopolar and bipolar stimulation condition. Again, the current amplitudes required for behavioral detection were lowest with infragranular corticoefferent excitation.