Impairment of cognitive function by chemotherapy: association with the disruption of phase-locking and synchronization in anterior cingulate cortex

Abstract

Background: Patients following prolonged cancer chemotherapy are at high risk of emotional and cognitive deficits. Research indicates that the brain neuronal temporal coding and synaptic long-term potentiation (LTP) are critical in memory and perception. We studied the effects of cisplatin on induction of LTP in the basolateral amygdala (BLA)-anterior cingulate cortex (ACC) pathway, characterized the coordination of spike timing with local theta oscillation, and identified synchrony in the BLA-ACC network integrity.

Results: In the study presented, the impacts of cisplatin on emotional and cognitive functions were investigated by elevated plus-maze test, Morris water maze test, and rat Iowa gambling task (RGT). Electrophysiological recordings were conducted to study long-term potentiation. Simultaneous recordings from multi-electrodes were performed to characterize the neural spike firing and ongoing theta oscillation of local field potential (LFP), and to clarify the synchronization of large scale of theta oscillation in the BLA-ACC pathway. Cisplatin-treated rats demonstrated anxiety- like behavior, exhibited impaired spatial reference memory. RGT showed decrease of the percentage of good decision-makers, and increase in the percentage of maladaptive behavior (delay-good decision-makers plus poor decision-makers). Cisplatin suppressed the LTP, and disrupted the phase-locking of ACC single neural firings to the ongoing theta oscillation; further, cisplatin interrupted the synchrony in the BLA-ACC pathway.

Conclusions: We provide the first direct evidence that the cisplatin interrupts theta-frequency phase-locking of ACC neurons. The block of LTP and disruption of synchronized theta oscillations in the BLA-ACC pathway are associated with emotional and cognitive deficits in rats, following cancer chemotherapy.

Fig. 1

Anxiety-like behavior in cisplatin treated rats as determined in the OFT and the EPM. a Total horizontal distance traveled, (b) the number of rearings, (c) the time of spent in the center, (d) the number of entries into the center, and (h) freezing time in an OFT, (e) time spent in open arms, (f) percentage of time spent into open arms versus closed arms and (g) freezing time for the EPM. Values are given as means + SEM. n = 17 for controls and n = 19 for cisplatin-treated rats. An asterisk indicates levels of significance for the difference between controls and cisplatin-treated rats. * p < 0.05. ** p < 0.01, *** p < 0.001 vs. control rats

Fig. 2

Spatial reference learning and memory impairment observed in cisplatin-treated rats exposed to the water maze test. a - b In the probe training sessions, the acquisition curve of cisplatin rats was impaired compared with control rats. c - d In 60 s probe tests, cisplatin-treated rats spent significantly lower percentage of time in the quadrant previously containing the platform than control rats, suggesting impaired memory. An asterisk indicates levels of significance for the difference between controls and cisplatin-treated rats.* p < 0.05, ** p < 0.01

Fig. 3

Changes in decision-making behavior induced by cisplatin using a rat Iowa gambling task. a – b Time course of percentage of advantageous choices for good (white), delayed good (grid), undecided (30 % gray) and poor (black) decision-makers during a 60 min RGT testing in control (A circles) and cisplatin (B squares) rats. Within the first 10 min, rats chose equally between advantageous and disadvantageous choices. They then quickly developed four distinct subgroups based on the percentage of advantageous choices during the 60 min test (>70 % preference of advantageous choices at 30 min and in the last 20 min for good decision-maker, < 70 % preference of advantageous choices at 30 min and > 70 % preference in the last 20 min for delayed good decision-maker, < 30 % in the last 20 min for poor decision-maker, and 30 - 70 % in the last 20 min for undecided maker). c Proportions of good performers (white bar), delayed good performers (grid bar), undecided behavior (30 % gray bar) and poor decision-making (black bar) for control group and cisplatin group. Advantageous choices (%) = numbers of nose-poke for choices (C + D) / numbers of nose-poke for choices (A + B + C + D) * 100 %. n = 24 for control group, n = 35 for cisplatin group

Fig. 4

Long-term potentiation (LTP)-like plasticity in the basolateral amygdala (BLA)-ACC synapse was impaired in cisplatin-treated rats. a Representative ACC evoked local field potential (LFP) responses to different-intensity BLA stimuli (200, 400 and 800 μA) in both control and cisplatin rats. b Averaged input/output (I/O) curves of BLA-ACC evoked LFP showed no significant alteration between control and cisplatin-treated rats. c Examples of LFP responses in the ACC to BLA stimuli before (pre-) and 40 min after (post-) theta burst stimulation (TBS) in control and cisplatin-treated rats. d LTP was reliably induced in control rats (n = 5). But in cisplatin-treated rats, the LTP induction was impaired when tested with a stimulate intensity that evoked about 50 % of the maximum LFP amplitude (n = 6). Results are expressed as mean ± SEM

Fig. 5

Enhanced the power of ACC theta-band oscillation (4–10 Hz) in cisplatin-treated rats. a The 16 channels LFP oscillations in the theta band frequencies recorded from the ACC. b The averaged power spectral density (PSD) showing a wider band of frequencies (0–15 Hz) in control and cisplatin-treated rats during spontaneous and CRD conditions. The main peaks of the PSD located during 1–4 Hz (delta band), the second peaks as magnified in the inset show power distributions in the 4–10 Hz (theta band) in different groups. c The average AUC of theta band PSD in control and cisplatin-treated rats showing increases in theta-band oscillation (4–10 Hz) power during both spontaneous and CRD stimulate conditions in cisplatin rats. d The histogram shows the enhancement of theta/delta ratio (theta/(theta + delta) in cisplatin rats. Data are expressed as mean ± SEM. # p < 0.05 vs. control

Fig. 6

Cisplatin disrupted the spikes phase-locking in the ACC. a Test of significance of phase-locking as a function of frequency (1 – 64 Hz). The threshold (red line) for significant phase-locking was set to p = 0.0023 (0.05/22, Bonferroni corrected). The shown phase-locked neuron in the control rat (gray line) exhibited maximal phase-locking at 9.5 Hz while the un-phase-locked neuron in the cisplatin-treated rat (black line) showed no significant phase-locking in theta range. b Histogram of the preferred phase of all phase-locked neurons in the control rats (n = 53 of 120). The figure shows most phase-locked neurons preferred to fire during the descending phase or at the trough of the oscillation. The red line is a schematic of the theta cycle. c The polar-histogram of the spike-field phase distribution of the phase-locked neuron from the control rat shown in (A). The figure shows the majority of spikes of this neuron fired close to 180°. The mean phase shown by the red arrows indicates this neuron preferred firing at 184° of the theta oscillation. The vector length R = 0.23. d Polar-histogram of the spike-field phase distribution of the un-locked neuron from the cisplatin-treated rat shown in (A). The figure shows this neurons action potential firing at random angles of the theta cycle oscillations suggesting disrupted phase-locking in rats following cisplatin treatment. The vector length R = 0.03

Fig. 7

Desynchronized theta activities between the BLA and ACC in cisplatin rats. a Representative traces of spontaneous theta band field potential in the BLA (black line) and ACC (blue line) in control (left) and cisplatin (right) rats. b Time-varying power spectra of BLA (upper) and ACC (bottom) LFP_θs in control and cisplatin rats. c The averaged cross-correlograms of control and cisplatin rats for both spontaneous activity and during visceral pain stimulation (60 mmHg CRD). d Statistical analysis revealed that the cross-correlation value (the second positive peak) was decreased in spontaneous theta activity in cisplatin-treated rats compared with control group. Meanwhile, in control rats, CRD significantly enhanced the correlation value when compared with spontaneous activity. In cisplatin rats there was no changing during CRD stimuli compared with resting state. Data are expressed as mean ± SEM. *, # p < 0.05