Persistent hyperdopaminergia decreases the peak frequency of hippocampal theta oscillations during quiet waking and REM sleep

Abstract

Long-term changes in dopaminergic signaling are thought to underlie the pathophysiology of a number of psychiatric disorders. Several conditions are associated with cognitive deficits such as disturbances in attention processes and learning and memory, suggesting that persistent changes in dopaminergic signaling may alter neural mechanisms underlying these processes. Dopamine transporter knockout (DAT-KO) mice exhibit a persistent five-fold increase in extracellular dopamine levels. Here, we demonstrate that DAT-KO mice display lower hippocampal theta oscillation frequencies during baseline periods of waking and rapid-eye movement sleep. These altered theta oscillations are not reversed via treatment with the antidopaminergic agent haloperidol. Thus, we propose that persistent hyperdopaminergia, together with secondary alterations in other neuromodulatory systems, results in lower frequency activity in neural systems responsible for various cognitive processes.

Figure 1. Altered HTOs in hyperdopaminergic mice.

Mean hippocampal LFP power distributions were calculated in the 2–12 Hz range for each mouse across the behavioral periods of interest. The images depict normalized power spectral distributions averaged across animals within genotype. Two way ANOVA of HTO frequency found the main effects of genotype [F_1,49 = 21.66, p<0.01] and condition [F_4,49 = 82.82, p<0.01], as well as the genotype by condition interaction [F_4,49 = 9.96, p<0.01] to be significant. Post-hoc tests revealed that DAT-KO mice display lower hippocampal theta oscillation (HTO) frequencies than WT mice during (A) baseline waking (p<0.01) and (B) REM sleep periods (p = 0.011), but not (C) waking periods immediately following novelty exposure (p = 0.35). Locomotor activity measured during the A) habituated and C) novelty exposed waking states are depicted in insets, and behavioral statistics are shown in Fig. 2F. One way ANOVA found significant effects when mice were exposed to a novel environment for both DAT-KO [F_4,24 = 54.47, p<0.01] and WT mice [F_4,24 = 31.19, p<0.001]. Newman-Keuls tests showed that peak HTO frequencies increased with novelty exposure for both genotypes (DAT-KO: N-K₂₀ = 3.92, WT: N-K₂₀ = 2.35). Error bars represent S.E.M for normalized theta power determined for each frequency across animals within a genotype; n = 11 for both genotypes. Two way ANOVA of total theta power found the main effects of genotype [F_1,39 = 15.21, p<0.01] and condition [F_3,39 = 4.55, p<0.01], as well as the genotype by wake-state interaction [F_3,39 = 6.46, p<0.01] to be significant. Post-hoc tests revealed that total theta power was not different between DAT-KO and WT mice during the baseline waking period (p>0.1); however, it was significantly higher in DAT-KO mice than WT mice following novelty exposure (p<0.01). One way ANOVA's found significant effects of condition for DAT-KO [F_3,19 = 8.22, p<0.01] but not WT mice [F_3,19 = 2.05, p>0.05]. Newman-Keuls tests showed that novelty exposure increased total theta power in DAT-KO (N-K₁₀ = 4.66).

Figure 2. The effect of psychoactive agents on HTO frequencies in WT and DAT-KO mice.

Hippocampal LFP power distributions were calculated in the 2–12 Hz range for each mouse across the drug treatment of interest. The images depict normalized power spectral distributions averaged across animals within genotype and drug treatment. Treatment with haloperidol 0.3 mg/kg (HAL) significantly attenuated novelty induced peak HTO frequencies increases in both (A) WT (N-K₂₀ = 3.39) and (B) DAT-KO (N-K₂₀ = 3.29) mice, and treatment with d-amphetamine 3.0 mg/kg (AMPH) attenuated novelty induced peak HTO frequency increases in both (C) WT (N-K₂₀ = 3.06) and (D) DAT-KO (N-K₂₀ = 4.42) mice. (E) Novelty and psychoactive drug effects on total theta power. Treatment with AMPH, but not HAL, potentiated novelty-induced theta power in WT mice (AMPH: N-K₂₀ = 5.01, HAL: N-K₂₀ = 5.01). Novelty-induced theta power was attenuated by treatment with AMPH, and unaffected by treatment with HAL in DAT-KO mice (AMPH: N-K₂₀ = 5.66, and HAL: N-K₂₀ = 4.66, respectively). (F) Novelty and psychoactive drug effects on locomotor activity. WT and DAT-KO mice displayed similar behavioral profiles during baseline periods (tstat_1,8 = 0.96, p = 0.36). Novelty exposure induced behavioral hyperactivity in DAT-KO mice (tstat_1,8 = 2.39, p<0.05), compared to novelty exposed WT mice. HAL attenuated locomotor activity in both genotypes. AMPH attenuated locomotor activity in DAT-KO mice, and potentiated locomotor activity in WT mice. Error bars represent S.E.M for recordings within a genotype. # = p<0.05; compared to animals within genotype during the baseline period. * = p<0.05; compared to animals within genotype during the novelty exposed; n = 5 for all groups.