Hyperdopaminergia and NMDA receptor hypofunction disrupt neural phase signaling

Abstract

Neural phase signaling has gained attention as a putative coding mechanism through which the brain binds the activity of neurons across distributed brain areas to generate thoughts, percepts, and behaviors. Neural phase signaling has been shown to play a role in various cognitive processes, and it has been suggested that altered phase signaling may play a role in mediating the cognitive deficits observed across neuropsychiatric illness. Here, we investigated neural phase signaling in two mouse models of cognitive dysfunction: mice with genetically induced hyperdopaminergia [dopamine transporter knock-out (DAT-KO) mice] and mice with genetically induced NMDA receptor hypofunction [NMDA receptor subunit-1 knockdown (NR1-KD) mice]. Cognitive function in these mice was assessed using a radial-arm maze task, and local field potentials were recorded from dorsal hippocampus and prefrontal cortex as DAT-KO mice, NR1-KD mice, and their littermate controls engaged in behavioral exploration. Our results demonstrate that both DAT-KO and NR1-KD mice display deficits in spatial cognitive performance. Moreover, we show that persistent hyperdopaminergia alters interstructural phase signaling, whereas NMDA receptor hypofunction alters interstructural and intrastructural phase signaling. These results demonstrate that dopamine and NMDA receptor dependent glutamate signaling play a critical role in coordinating neural phase signaling, and encourage further studies to investigate the role that deficits in phase signaling play in mediating cognitive dysfunction.

Figure 1.

Low- and high-frequency phase synchrony across the hippocampus–prefrontal cortex pathway. Electrophysiological recordings were conducted in WT mice as they explored a novel environment. a, Hippocampus and prelimbic cortex LFP oscillations were filtered in the theta (4–10 Hz) and gamma (33–55 Hz) frequency range, and phase time series were extracted via Hilbert transform. b, Three second trace of theta filtered HP and PrL LFP oscillations demonstrating periods of instantaneous phase synchrony (denoted by red dashes). c, Histogram of all of the instantaneous theta phase offset values observed between a single HP and PrL electrode pair. Phase synchrony was quantified for each HP and PrL electrode pair by calculating the Rayleigh statistic for the instantaneous phase offset values observed between the two electrodes within the frequency range of interest, where the Z-stat = −ln(P). d–g, Distribution of Z-stats corresponding to (d, e) theta band and (f, g) gamma band phase synchrony values measured across all HP-PrL electrode pairs while WT mice were in the novel environment (left) and home cage (right). All of the HP-PrL combinations (320/320) demonstrated significant theta band phase synchrony in the novel environment. Novelty exposure significantly enhanced theta band phase synchrony when compared with theta band phase synchrony values measured while mice were in their home cage. The majority of HP-PrL LFP combinations (285/320) demonstrated significant gamma band phase synchrony. Novelty exposure significantly diminished gamma band phase synchrony when compared with gamma band phase synchrony values measured while mice were in their home cage. h, Introduction of temporal offsets >500 ms between HP and PrL LFP's abolished theta phase synchrony. i, Introduction of temporal offsets >40 ms between HP and PrL LFP's abolished gamma phase synchrony (see inset).

Figure 2.

Phasic modulation of gamma oscillations by theta oscillations. a, Two second hippocampal theta oscillation trace (green) overlaid on simultaneously recorded gamma oscillations (red) and the gamma oscillation amplitude envelope (black). Red arrows show bouts of increased gamma oscillation amplitudes that were phase coupled to theta oscillation troughs. b, Sample of hippocampal LFP channel that did not display theta-gamma coupling. Notice peaks in gamma oscillatory power are not consistent with a theta oscillation phase. c, d, The modulation index M was determined for all hippocampal (c) and cortical LFP channels (d) while mice were in their home cage and exploring a novel environment. Novelty exposure potentiated hippocampal and cortical theta-gamma coupling in WT mice. e, Coupling between hippocampal theta oscillations and cortical gamma oscillations was quantified using the modulation index M. Only 2/232 HP-PrL channel combinations demonstrated significant modulation in the home cage; conversely, 39/240 HP-PrL channel combinations demonstrated significant theta-gamma modulation in the novel environment.

Figure 3.

Persistent hyperdopaminergia disrupts spatial cognitive performance. Spatial cognitive performance was measured using an eight-arm radial maze task across five 4 d trial blocks. a, b, DAT-KO mice displayed deficits in cognitive performance as measured by the number of arms entered before a repeat entry (a) and cognitive inflexibility as measured by the number of perseverative errors committed during task performance (b). Data are presented as mean ± SEM; n = 7 for both groups. *p < 0.05 for single comparisons across genotype using ANOVA followed by Student's t test.

Figure 4.

HP-PrL gamma phase synchrony is potentiated in DAT-KO mice. Electrophysiological recordings were conducted in WT mice as they explored a novel environment. a–d, Distribution of Z-stat corresponding to theta band (a, b) and gamma band (c, d) phase synchrony values measured across all HP-PrL electrode pairs while mice were in the novel environment (left) and home cage (right). DAT-KO mice displayed significantly higher HP-PrL gamma phase synchrony than novelty exposed WT mice. Theta band phase synchrony remained unchanged. e, Novelty exposure increased theta-band synchrony in DAT-KO mice but failed to attenuate gamma band phase synchrony. Gamma band HP-PrL coherence and PrL to HP partial directed LFP coherence was significantly increased in DAT-KO mice. Red bars indicate significance thresholds at *p < 0.01.

Figure 5.

NMDA receptor hypofunction disrupts hippocampal and prefrontal cortical-dependent cognitive function. Spatial cognitive performance was measured using an eight-arm radial maze task across five 4 d trial blocks. a, b, NR1-KD mice displayed deficits in cognitive performance as measured by the number of arms entered before a repeat entry (a) and cognitive inflexibility as measured by the number of perseverative errors committed during task performance (b). Data are presented as mean ± SEM; n = 7 and 8 for WT and NR1-KD mice, respectively. *p < 0.05 for single comparisons across genotype using mixed ANOVA followed by Student's t test.

Figure 6.

NR1-KD mice displayed attenuated theta-gamma phase coupling. Electrophysiological recordings were conducted in WT mice as they explored a novel environment. a, b, NR1-KD displayed significantly attenuated hippocampal (a) and cortical (b) theta-gamma coupling compared with WT mice. Additionally, novelty exposure failed to potentiate hippocampal and cortical theta-gamma coupling strength in NR1-KD mice when compared with data recorded while mice were in their home cage. c, Phase modulation of hippocampal LFP channels clustered at two preferred phases in WT mice (α and β, demarcated by vertical dashed lines). NR1-KD mice displayed disrupted hippocampal α phase but not β phase modulation. Each WT animal had multiple hippocampal LFP channels that displayed α phase modulation. d, Phase modulation of cortical LFP channels occurred at one preferred phase in WT and NR1-KD mice (α, demarcated by vertical dashed lines). e, Coupling between hippocampal theta oscillations and cortical gamma oscillations was quantified using the modulation index M. NR1-KD mice displayed enhanced interstructural theta-gamma modulation in the novel environment (111/304 significantly modulated channel combinations) and home cage (111/176 significantly modulated channel combinations) compared with WT mice.

Figure 7.

Model of novelty, dopamine, and NMDA receptor hypofunction effects on neural phase signaling. a, WT mice show high HP–PF gamma band synchrony, low HP–PF theta band phase synchrony, and low theta-gamma phase coupling in their home cage. b, Novelty exposure potentiates HP–PF theta band synchrony, theta-gamma intrastructural phase coupling, theta-gamma interstructural phase coupling, and attenuates HP–PF gamma band synchrony in WT mice. c, HP–PF gamma band interstructural phase synchrony is potentiated in DAT-KO mice. d, HP and PF intrastructural phase coupling is disrupted in NR1-KD mice, and HP and PF interstructural phase coupling is enhanced in NR1-KD mice.