Long-term modification of cortical synapses improves sensory perception

Abstract

Synapses and receptive fields of the cerebral cortex are plastic. However, changes to specific inputs must be coordinated within neural networks to ensure that excitability and feature selectivity are appropriately configured for perception of the sensory environment. We induced long-lasting enhancements and decrements to excitatory synaptic strength in rat primary auditory cortex by pairing acoustic stimuli with activation of the nucleus basalis neuromodulatory system. Here we report that these synaptic modifications were approximately balanced across individual receptive fields, conserving mean excitation while reducing overall response variability. Decreased response variability should increase detection and recognition of near-threshold or previously imperceptible stimuli. We confirmed both of these hypotheses in behaving animals. Thus, modification of cortical inputs leads to wide-scale synaptic changes, which are related to improved sensory perception and enhanced behavioral performance.

Figure 1

Example of AI synaptic receptive field modification induced by nucleus basalis pairing. a, Experimental preparation. b, Example of synaptic tuning curve modification induced by nucleus basalis pairing. Top, intensity sensitivity at 4 kHz. Bottom, frequency tuning at 30 dB SPL. Responses to paired stimulus (30 dB SPL, 4 kHz; arrow) are enhanced while responses to peak level and best frequency (arrowheads) are reduced. c, Frequency-intensity synaptic receptive field for same cell in b. Top, before (left) and after (right) pairing. Color, EPSC amplitude. Blue lines, threshold. Bottom, change in EPSCs (post-pairing–pre-pairing). Excitation at paired tone (circle) increased from −14.8±3.6 pA to – 46.8±6.6 pA (p<0.01, Student’s paired two-tailed t-test); excitation at original best stimulus (80 dB SPL, 16 kHz; square) decreased from −98.6±15.4 pA to −43.3±8.1 pA (p<0.01). Net excitation across stimuli was similar before and after pairing (before: −1.68 nA, after: −1.51 nA, p>0.4). Scale: 50 pA, 40 msec. Error bars show s.e.m.

Figure 2

Conservation of total excitation after pairing. a, Intensity-specific changes. Top, summary of changes relative to paired level over all recordings (arrow; increase of 66.7%±10.3%, n=29 neurons, p<10⁻⁶, Student’s paired two-tailed t-test). Significant potentiation also occurred to responses evoked by stimuli of the paired frequency and −10 dB lower in intensity (29.7%±12.4%, p<0.04). Bottom, changes to original peak level (arrowhead; decrease of −19.0%±5.2%, p<10⁻⁴). b, Frequency-specific changes. Top, changes relative to paired frequency. Bottom, changes to original best frequency (−21.9%±5.7%, p<0.001). Same recordings as in a. c, Time course of changes to paired (circles) and original best stimuli (squares). Horizontal bar, pairing. Same recordings as in a. d, Conservation of total excitation after pairing. Before and after pairing, relative amounts of increases (black) and decreases (white) in synaptic strength were similar across the entire frequency-intensity synaptic receptive field (excitation increased by a factor of 3.2±0.9 and decreased by −4.5±1.2; n=29 neurons, p>0.6, Mann-Whitney), across intensity at paired frequency (increase: 1.2±0.3, decrease:−1.3±0.2; p>0.6), and across frequency at paired intensity (increase: 1.1±0.1, decrease:−1.1±0.2; p>0.5). Same recordings as a. Error bars show s.e.m.

Figure 3

Best stimuli depression depends on recent sensory experience. a, Example recording in which for ten minutes post-pairing, no stimuli >60 dB SPL were presented (hatching). Responses to paired tone (30 dB SPL, 4 kHz; circle) increased (before: −21.3 pA, after: −40.7 pA), responses to absolute best stimulus (80 dB SPL, 1 kHz) were unchanged (before: −79.4 pA, after: −81.1 pA; square), responses to 60 dB SPL, 2 kHz tones (relative best stimuli) decreased (before: −54.3 pA, after: −26.0 pA; diamond). b, Summary of reduced stimulus set experiments. Left, EPSCs evoked by relative best stimuli depressed (−23.6±5.9%, n=13 neurons, p<0.006, Student’s paired two-tailed t-test), while absolute best stimuli were unchanged (−6.2±4.3%, p>0.1). Right, best stimuli depression was equivalent after 51-60 presentations regardless of rate (black bars; 0.05 Hz: −27.2±4.7%, n=7 neurons, p<0.002; 0.1 Hz: −39.5±5.8%, n=5 neurons, p<0.003; 0.5 Hz: −31.9±7.2%, n=10 neurons, p<0.003; equivalent magnitudes across rates, p>0.4, Krusal-Wallis H=1.51). No depression was measurable after 11-20 presentations (open bars). Error bars show s.e.m.

Figure 4

Pairing decreases synaptic variance to enhance detection and recognition of sensory stimuli. a, Example of detection changes. Top, responses to paired frequency (tonal presentation, red). Scale: 40 pA, 60 msec. Bottom, distributions of tone-evoked and spontaneous EPSCs before (left, dashed) and after (right, solid) pairing. Before pairing, signal and noise distributions overlapped (mutual information MI_pre: 0.17 bits), and had higher variability q in signal distribution (q_pre: 24.8 pA, μ_pre: −30.7 pA, σ²_pre : 761.5 pA²). After pairing, variability decreased and MI increased (MI_post: 0.26 bits, q_post: 15.1 pA, μ_post: −26.2 pA, σ²_post : 396.9 pA²). b, Example of recognition changes. Top, responses evoked by tones of different frequencies (paired tone, red). Scale: 50 pA, 30 msec. Bottom, EPSC distributions for paired (red) and unpaired tones (gray). Initially (left), paired and unpaired responses were similar (MI_pre: 0.07 bits, q_pre: 69.0 pA, μ_pre: −42.2 pA, σ²_pre: 2911.3 pA²). After pairing, means increased while variability decreased, enhancing MI between paired and unpaired distributions (MI_post: 0.18 bits, q_post: 25.9 pA, μ_post: −72.2 pA, σ²_post : 1871.7 pA²). c, Changes to detection. Top left, MI between signal and noise increased after pairing (before: 0.19±0.02 bits, after: 0.23±0.03 bits, z=−2.0, n=29, p<0.05, two-tailed paired Wilcoxon signed rank test). Top right, q decreased after pairing (before: 19.2±4.6 pA, after: 12.7±3.3 pA, z=2.8, p<0.005). Bottom left, mean amplitudes of signal distributions were unchanged after pairing (before: −33.4±5.3 pA, after: −34.0±5.2 pA, z=−0.7, p>0.5). Bottom right, standard deviations of signal distributions decreased after pairing (before: 24.0±4.8 pA, after: 19.3±3.8 pA, z=2.4, p<0.02). d, Changes to recognition. Top left, MI between paired and unpaired stimuli increased (before: 0.05±0.01 bits, after: 0.08±0.01 bits, z=−3.0, p<0.003). Top right, q decreased after pairing (before: 11.2±3.1 pA, after: 6.2±2.0 pA, z=2.5, p<0.02). Bottom left, mean amplitudes of paired stimuli responses increased after pairing (before: −27.9±4.2 pA, after: −44.5±6.9 pA, z=−4.4, p<10⁻⁴). Bottom right, standard deviations of paired stimuli responses were unchanged (before: 15.6±3.2 pA, after: 14.2±3.1 pA, z=0.9, p>0.3).

Figure 5

Nucleus basalis pairing modifies spiking receptive fields. a, Suprathreshold intensity sensitivity (at 16 kHz) is modified after pairing. Example recording in which responses at paired intensity (50 dB SPL, arrow) increased (before: 1.3±0.3 spikes/tone, after: 2.6±0.6 spikes/tone, p<0.03, Student’s paired two-tailed t-test), responses at 80 dB SPL (arrowhead) decreased (before: 3.1±0.6 spikes/tone, after: 1.9±0.4 spikes/tone, p<0.05). Scale: 5 mV, 50 msec. b, Example of changes to suprathreshold frequency tuning (at 60 dB SPL) after pairing (paired frequency 16 kHz, before: 0.5±0.1 spikes/tone, after: 1.6±0.1 spikes/tone, p<10⁻⁴; best frequency 4 kHz, before: 1.8±0.1 spikes/tone, after: 1.2±0.1 spikes/tone, p<0.001). Scale: 20 mV, 25 msec. c, Summary of current-clamp recordings. Spiking responses to paired tones increased (65.2±17.6%, n=14 neurons, p<0.003), responses to original best stimuli decreased (−26.7±7.4%, p<0.004); no net change in spiking (0.2±10.3%, p>0.9). d, Summary of changes to MI after pairing. Pairing increased MI for detection (before: 0.29±0.06 bits, after: 0.46±0.08 bits, z=−2.3, p<0.02; left) and recognition (before: 0.16±0.04 bits, after: 0.29±0.05 bits, z=−2.9, p<0.004; right). Error bars show s.e.m.

Figure 6

Nucleus basalis pairing improves auditory detection. a, Example of enhanced detection after pairing. Hits (circles) at 30 dB SPL increased after pairing (before pairing, black: 28.9±6.6%, after, red: 66.7±10.0%, p<0.005). Responses to foils (triangles) were unchanged (false alarms at 30 dB SPL before, black: 18.7±3.2%, after, red: 16.7±5.7%, p>0.7). d’ increased (0.3 to 1.4). b, Carbachol pairing enhanced detection without nucleus basalis stimulation. Hits increased (before: 36.7±6.6%, after: 74.1±7.8%, p<0.001), false alarms were unchanged (before: 32.4±7.6%, after: 27.2±4.1%, p>0.5). d’ increased (0.1 to 1.3). c, Summary of d’ values before and after pairing nucleus basalis stimulation with saline (filled squares; d’ before: 0.7±0.2, after: 1.5±0.3, N=9 animals, p<0.003), or carbachol pairing without nucleus basalis stimulation (open squares; d’ before: 1.0±0.5, after: 2.0±0.5, N=7, p<0.03). Saline pairing without nucleus basalis stimulation had no effect (d’ before: 1.2±0.6, after: 1.2±0.7, N=4, p>0.8). d, Changes to mean response rate across animals. Response rate increased after pairing at the paired intensity level (hits before pairing: 47.7±4.7%, after: 70.6±4.0%, N=9, p<0.002), and–10 dB SPL from paired level (before: 28.9±6.4%, after: 42.4±6.7%, p<0.03), but not at higher intensities (p>0.1). False alarms were unchanged (before: 25.2±4.6%, after: 22.1±5.5%, p>0.3). e, d’ for paired stimuli across animals was enhanced after pairing (before: 0.7±0.2, after: 1.5±0.3, p<0.003). f, Comparison of detection before pairing on first and second days (d’ day one: 0.6±0.2, d’ day two: 0.8±0.2, N=9, p>0.4; filled squares) and animals receiving only saline (d’ day one: 1.2±0.6, d’ day two: 1.3±0.6, N=4, p>0.2; open squares). g, Atropine prevented effects of pairing. Hits, false alarms, and d’ were unchanged (p>0.6). h, AP5 prevented effects of pairing (p>0.5). i, Summary of atropine (filled diamonds; d’ before: 0.7±0.4, after: 1.0±0.2, N=4, p>0.2) and AP5 (open diamonds; d’ before: 0.9±0.2, after: 0.7±0.4, N=4, p>0.4). Error bars show s.e.m.

Figure 7

Nucleus basalis pairing improves recognition. a, Responses from one animal. Nucleus basalis pairing did not improve ‘wideband’ performance (d’ before: 3.5, after: 2.8). b, Responses from another animal. Pairing improved ‘narrowband’ performance (d’ before: 1.3, after: 2.3). c, Summary of wideband (filled squares; d’ before: 2.7±0.3, after: 2.3±0.3, N=12, p>0.3) and narrowband (open squares; d’ before: 0.5±0.1, after: 1.0±0.2, N=12, p<0.005). d, Wideband performance was unchanged after pairing (hits before pairing: 90.3±2.8%, after: 84.5±5.0%, N=12, p>0.1). e, Narrowband performance was improved after pairing (hits before pairing: 50.1±6.6%, after: 69.9±9.0%, N=12, p<0.005). f, d’ before (black) and after pairing (red) for wideband (before: 2.7±0.3, after: 2.3±0.3, p>0.3) and narrowband (before: 0.5±0.1, after: 1.0±0.2, p<0.005) tasks. g, Atropine infused into AI prevented pairing from improving narrowband behavior (hits before pairing: 72.0±16.4%, after: 63.6±9.5%, p>0.6; false alarms before: 23.4±6.5%, after: 14.6±6.4%, p>0.3; d’ before: 1.3, after: 1.4). h, When only lower intensity (<50 dB SPL) stimuli were presented 30 minutes post-pairing, narrowband behavior task was unaffected (hits before: 23.3±15.4%, after: 11.5±9.5%, p>0.3; false alarms before: 11.9±4.5%, after: 7.5±1.8%, p>0.3; d’ before: 0.4, after: 0.2). i, Summary of AI atropine (filled diamonds; d’ before: 0.7±0.3, after: 0.8±0.3, N=5, p>0.05), systemic atropine (open diamonds; d’ before: 1.2±0.7, after: 1.0±0.6, N=5, p>0.3), or when only quiet stimuli were presented post-pairing (filled triangles; d’ before: 0.7±0.2, after: 0.3±0.1, N=6, p>0.05). Error bars show s.e.m.

Figure 8

Pairing under anesthesia improves perception. a, Detection; animal anesthetized with pentobarbital during pairing. Hits increased after pairing (before: 30.6±16.3%, after: 67.3±6.5%, p<0.04). False alarms were unchanged after pairing (before: 27.2±5.2%, after: 27.3±1.9%, p>0.4), increasing d’ from 0.4 to 0.8. . b, Narrowband; pentobarbital anesthesia during pairing. Hits increased (before: 39.0±2.7%, after: 63.5±7.9%, p<0.03), false alarms were unchanged (before: 20.9±2.9%, after: 22.4±3.5%, p>0.7), increasing d’ from 0.6 to 1.1. c, Wideband; pentobarbital anesthesia during pairing (hits before: 54.8±11.9%, after: 75.1±1.1%, p>0.1; false alarms before: 6.8±1.7%, after: 4.3±2.0%, p>0.3; d’ before: 1.7, after: 1.8). d, Summary of experiments with pentobarbital anesthesia during and 1-3 hours post-pairing. Performance on wideband (triangles), narrowband (inverted triangles), and detection (squares) tasks was assessed 30-60 minutes pre-pairing and 1-2 hours after recovery. Performance improved on detection (d’ before: 0.9±0.1, after: 1.3±0.2, N=7, p<0.03) and narrowband recognition (d’ before: 0.4±0.1, after: 0.7±0.2, N=5, p<0.02), but not wideband (d’ before: 1.6±0.2, after: 2.0±0.4, N=5, p>0.05). e, Detection; animal anesthetized with isoflurane before pairing. Hits increased after pairing (before: 53.3±3.3%, after: 83.3±9.6%, p<0.03). False alarms were unchanged (before: 15.1±2.6%, after: 20.7±4.0%, p>0.1), increasing d’ from 0.8 to 1.4. f, Narrowband recognition; animal anesthetized with isoflurane during pairing. Hits increased (before: 36.8±5.5%, after: 62.1±9.4%, p<0.04), false alarms were unchanged (before: 30.6±3.6%, after: 36.1±4.2%, p>0.1), increasing d’ from 0.2 to 0.7. g, Wideband recognition; animal anesthetized with isoflurane during pairing. Behavior was unchanged (hits before: 69.4±12.3%, after: 74.7±5.4%, p>0.7; false alarms before: 9.2±1.9%, after: 11.9±2.2%, p>0.3; d’ before pairing: 1.8, after: 1.8). h, Summary of experiments with isoflurane anesthesia during pairing. Performance improved on detection (d’ before: 1.1±0.4, after: 1.7±0.5, N=6, p<0.04) and narrowband (d’ before: 0.2±0.2, after: 0.5±0.1, N=5, p<0.05), but not wideband (d’ before: 1.5±0.2, after: 1.9±0.1, N=3, p>0.1). Error bars show s.e.m.