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.2011 Oct 26;31(43):15560-8.
doi: 10.1523/JNEUROSCI.2970-11.2011.

Dysfunctional prefrontal cortical network activity and interactions following cannabinoid receptor activation

Affiliations

Dysfunctional prefrontal cortical network activity and interactions following cannabinoid receptor activation

Michal T Kucewicz et al. J Neurosci..

Abstract

Coordinated activity spanning anatomically distributed neuronal networks underpins cognition and mediates limbic-cortical interactions during learning, memory, and decision-making. We used CP55940, a potent agonist of brain cannabinoid receptors known to disrupt coordinated activity in hippocampus, to investigate the roles of network oscillations during hippocampal and medial prefrontal cortical (mPFC) interactions in rats. During quiet wakefulness and rest, CP55940 dose-dependently reduced 0.1-30 Hz local field potential power in CA1 of the hippocampus while concurrently decreasing 30-100 Hz power in mPFC; these contrasting population-level effects were paralleled by differential effects on underlying single-unit activity in the two structures. During decision-making phases of a spatial working memory task, CP5540-induced deficits in hippocampal theta and prefrontal gamma oscillations were observed alongside disrupted theta-frequency coherence between the two structures. These changes in coordinated limbic-cortical network activities correlated with (1) reduced accuracy of task performance, (2) impaired phase-locking of prefrontal single-unit spiking to the local gamma and hippocampal theta rhythms, and (3) impaired task-dependent activity in a subset of mPFC units. In addition to highlighting the importance of CA1-mPFC network oscillations for cognition, these results implicate disrupted theta-frequency coordination of CA1-mPFC activity in the cognitive deficits caused by exogenous activation of brain cannabinoid receptors.

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Figures

Figure 1.
Figure 1.
Extracellular tetrode recordings of single-unit activity.a, Representative micrographs of Giemsa-stained 50 μm brain slices showing the sites ofpost hoc electrolytic lesions (arrowheads) in the principal cell layer of the dorsal CA1 (left) and prelimbic subdivision of the medial prefrontal cortex (right) fitted to a schematic of corresponding rat brain section (from rat brain atlas by Paxinos and Watson, 1998).b, Thirteen color-coded clusters of action potentials spread along the axes of relative energy recorded on two channels of a tetrode in CA1. The properties of the red cluster (circled) are shown inc andd.c, Mean waveform recorded on color-coded channels of the tetrode (top) showing stable relative spike amplitudes throughout one T-maze experiment (bottom). Note the behavioral modulation of firing rate during the first (predrug) and the second (postdrug) T-maze epochs (horizontal black bars). Dashed vertical line marks the time of drug administration.d, Distribution of interspike intervals (ISI) and autocorrelogram for all spikes fired by the unit in the experimental session. Notice the characteristic hippocampal theta modulation of unit firing (∼100 ms interspike intervals).
Figure 2.
Figure 2.
Cannabinoid receptor activation causes differential changes in network oscillations and single-unit activity in CA1 and mPFC. Data from simultaneous CA1 and mPFC recordings are presented on the left and right, respectively.a, Power spectrograms (1 Hz bandwidth, 5 s sliding time window with 2 s overlap) of local field potential oscillations (2–60 Hz range) throughout the course of one rest box experiment. White trace signifies the total power changes of the broadband LFP signal (0.1–475 Hz). Dashed vertical line marks the time of drug injection. Horizontal white bars indicate the preinjection (PRE) and postinjection (POST) intervals used for subsequent analyses of drug effects on LFP power and single-unit activity.b, Subject-averaged (N = 6) change in LFP power across a 125 Hz range of oscillations at three doses of CP55940 and its vehicle. Horizontal bars mark frequency ranges over which CP55940 caused significant, dose-dependent decreases in power (tested by repeated-measures ANOVA). Note the differential effects of the intermediate dose highlighted in dark red.c, Interspike interval (ISI) distributions comparing predrug and postdrug (black and red lines, respectively) single-unit activity following vehicle (n = 68 and 73 putative pyramidal cells in CA1 and mPFC respectively), 0.15 mgkg−1 (n = 62 and 59) or 0.30 mgkg−1 (n = 73 and 53) of CP55940.d, Cross-correlogram plots (10 ms bins) of all possible cell pair combinations accompanied by analogous plots from the vehicle control experiment, as inc. *p < 0.05, ***p < 0.001.
Figure 3.
Figure 3.
Hippocampal and prefrontal cortical LFP power changes in the spatial working memory task.a, Schematic diagram of the double-ended T-maze showing the path trajectory of one trial (magenta line) beginning in the guided-turn reward point (G), followed by central arm run with a turn decision point (dashed line) and ending in choice turn reward location (C) (see Materials and Methods).b, Accuracy of task performance before and after administration of the drug (0.15 mgkg−1) or its vehicle (N = 5). **p < 0.01.c,d, Spectrograms (2 Hz bandwidth, 1 s sliding time window with 0.01 s overlap) of LFP power changes in CA1 (c) and mPFC (d) on approach to the decision point (white dashed line) during trial-averaged choice runs (n = 17 and 15 trials) in one representative experiment before and after administration of 0.15 mgkg−1 of the drug. Horizontal white bars indicate the time interval used for all subsequent analyses.e, Subject-averaged (N = 5) change in LFP power (1 Hz bandwidth, 1 s time window) across the 100 Hz range of oscillations at one dose of CP55940 used (0.15 mgkg−1) and its vehicle. Horizontal bars span the theta and gamma frequency bands over which mean power was compared. *p < 0.05.
Figure 4.
Figure 4.
Disruption of hippocampal–prefrontal LFP coherence in the theta range correlates with behavioral impairment in the spatial working memory task.a, Coherograms (2 Hz bandwidth, 1 s sliding window with 0.1 s overlap) illustrating the effects of CP55940 (0.15 mgkg−1) on LFP coherence between CA1 and mPFC during runs toward the decision point (dashed line) from the same experiment corresponding to power spectrograms in Figure 3. Horizontal white bars indicate the time interval of choice run used for all subsequent analyses. Black arrowhead on the color scale points to 95% confidence level of coherence.b, Hippocampal–prefrontal LFP coherence (1 Hz bandwidth) over 2–30 Hz frequency range averaged over subjects (N = 5) following 0.15 mgkg−1 CP55940. Confidence level atp = 0.05 is delineated by black dashed line.c, Averaged 7–9 Hz coherence (N = 5) comparing drug effect in the vehicle (light gray) and 0.15 mgkg−1 (dark gray) experiments.d, Scatter plot of performance accuracy and corresponding mean hippocampal-prefrontal 7–9 Hz coherence from all 36 maze sessions. Black lines (continuous for all dataset; dashed for 0.15 mgkg−1 and 0.30 mgkg−1 data points) show Pearson's correlation analysis signifying positive correlation at the 0.01 level. *p < 0.05.
Figure 5.
Figure 5.
Single units display state-dependent deficits in phase-locking to specific bands of LFP oscillations.a, An example of one hippocampal unit showing preferential spiking (red tick marks) on distinct phases of the concurrent LFP oscillation (bandpass filtered for at 5–10 Hz) during a single choice central arm crossing. Rose diagram shows the distribution of spikes fired by the unit around the phases of the theta cycle. Theta phase-locking is quantified by circular-concentration coefficient (K).b, Mean population phase-locking of hippocampal and prefrontal single units (n = 41 and 47 cells) to three bands of their network LFP oscillations during preinjection and postinjection (0.15 mgkg−1) choice runs.c, Analogous bar plots showing mean population phase-locking of prefrontal units to hippocampal local field oscillations during preinjection and postinjection intervals (0.30 mgkg−1) of the rest box experiment (n = 53 cells) and during preinjection and postinjection session (0.15 mgkg−1) choice runs of the T-maze experiment (n = 47 cells). Note that the drug has a profound effect on the theta unit phase-locking only in the working memory condition, even though higher dose was used in the rest box condition. **p < 0.01.
Figure 6.
Figure 6.
CP55940-induced behavioral impairment in the spatial working memory task is accompanied by loss of turn-selective firing in prefrontal cortex.a, Schematic diagram of one correct left-turn trial run (magenta line) from the sample location (G) to the goal choice location (C). Below, Enlarged top views of subject-averaged (N = 5) central arm trajectories from correct predrug, incorrect predrug, and postdrug runs toward the decision point marked by vertical dashed line. Magenta and blue indicate left and right choice runs, respectively. The black bar indicates the last three segments of the central arm preceding the decision point. Note that the two trajectories are significantly separated in these last segments for the correct trials, but overlap for incorrect and postdrug conditions.b, Tracking data from one experiment showing left (magenta) and right (blue) choice predrug runs with position bins (divided by black lines) over which firing rates of single units were calculated.c, Firing rate of an example prefrontal turn-selective neuron during the corresponding choice runs shown inc. Note that the unit shows increased selective firing just before the decision point (dashed line), which is lost following the drug.d, Bar plot shows total fraction of all cells (n = 47 and 41 cells) showing turn-selective firing in CA1 and mPFC before and after the drug (0.15 mgkg−1). Dashed line signifies the expected 0.05 chance occurrence of turn-selective units. *p < 0.05.
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