Chemokine CCR5 and cocaine interactions in the brain: Cocaine enhances mesolimbic CCR5 mRNA levels and produces place preference and locomotor activation that are reduced by a CCR5 antagonist.

C-C chemokine receptor type 5, also known as CCR5 or CD195, is best known as a viral co-receptor that facilitates entry of HIV into cells. Evidence that CCR5 knockout mice display fewer dopamine neurons, lower striatal dopamine levels, and reduced locomotor activation compared to wild types also suggest a link between CCR5 receptors and cocaine dependence. Here, we tested the hypothesis using male Sprague-Dawley rats that cocaine-induced locomotor activation and conditioned place preference (CPP) are inhibited by a FDA-approved CCR5 antagonist (maraviroc), and that CCR5 gene expression in mesolimbic substrates is enhanced by repeated cocaine exposure. Pretreatment with maraviroc (1, 2.5, 5 mg/kg, IP) reduced hyperlocomotion induced by acute cocaine (10 mg/kg) without affecting spontaneous locomotor activity. For CPP experiments, rats conditioned with cocaine (10 mg/kg × 4 days, IP) were injected with maraviroc (1, 2.5, 5 mg/kg, IP) before each injection of cocaine. Maraviroc dose-dependently inhibited development of cocaine CPP, with a dose of 5 mg/kg producing a significant reduction. In rats treated repeatedly with cocaine (10 mg/kg × 4 days, IP), CCR5 gene expression was upregulated in the nucleus accumbens and ventral tegmental area but mRNA levels of CCR5 ligands (i.e., CCL3, CCL4 and CCL5) were not affected. Our results suggest that mesolimbic CCR5 receptors are dysregulated by cocaine exposure and, similar to CXCR4 and CCR2 receptors, influence behavioral effects related to the abuse liability of cocaine.

Place cell firing cannot support navigation without intact septal circuits.

Though it has been known for over half a century that interference with the normal activity of septohippocampal neurons can abolish hippocampal theta rhythmicity, a definitive answer to the question of its function has remained elusive. To clarify the role of septal circuits and theta in location-specific activity of place cells and spatial behavior, three drugs were delivered to the medial septum of rats: Tetracaine, a local anesthetic; muscimol, a GABA-A agonist; and gabazine, a GABA-A antagonist. All three drugs disrupted normal oscillatory activity in the hippocampus. However, tetracaine and muscimol both reduced spatial firing and interfered with the rat's ability to navigate to a hidden goal. After gabazine, location-specific firing was preserved in the absence of theta, but rats were unable to accurately locate the hidden goal. These results indicate that theta is unnecessary for location-specific firing of hippocampal cells, and that place cell activity cannot support accurate navigation when septal circuits are disrupted.

Place cell assemblies remain intact, despite reduced phase precession, after cholinergic disruption.

The hippocampal theta rhythm is frequently viewed as a clocking mechanism that coordinates the spiking activity of neurons across the hippocampus to form coherent neural assemblies. Phase precession is a form of temporal coding evidencing this mechanism and is degraded following systemic pharmacological disruption of cholinergic signaling. However, whether neural assemblies are commensurately degraded, as would be predicted from a clocking mechanism hypothesis, remains unknown. To address this, we recorded the spiking activity of hippocampal place cells as rats completed laps on a circle track for chocolate drink before versus during the influence of a systemic muscarinic acetylcholine receptor antagonist. We compared the integrity of hippocampal ensembles using three approaches. The first approach used cross-correlogram (CCG) analyses to ask if the relative spike-timing between pairs of cells became less reliable. The second used a general linear model based analysis to ask whether the activity of simultaneously recorded neurons became any less predictive of the spiking activity of single neurons. Finally, the third approach used a reconstruction analysis to ask if the population activity was any less informative regarding the environmental position of the animal and whether theta sequences were impaired. The results of all three analyses paint a consistent picture: systemic cholinergic disruption did not degrade assembly integrity. These data demonstrate that place cell assemblies do not depend upon high quality phase precession.

NMDA Receptor-Dependent Dynamics of Hippocampal Place Cell Ensembles.

The hippocampus is a key brain area to encoding and storing memories. Hippocampal place cells encode the position of an animal in space by firing when the subject is at a specific location in the environment. Therefore, place cells are considered essential to spatial memory and navigation. It has recently been revealed that place-cell activity is not constant even in a familiar environment, but changes dynamically over time. However, the mechanism behind these changes in activity is not yet fully understood. In this study, the activity of hippocampal CA1 neurons of male mice was tracked during repeated performances of a spatial task in a virtual reality environment. By comparing place-cell ensemble representations among repeated performance of the task, the overlap rate of the active place-cell population was found to be time dependent but independent of the number of tasks within a fixed time. These findings suggest that place codes change automatically and at a constant speed. Furthermore, the dynamics of place-cell activity were found to be suppressed by an NMDA receptor antagonist. In summary, the spontaneously dynamic nature of place-cell activity is at least in part regulated by NMDA receptors, and the dynamics may encode temporal information of episodes.SIGNIFICANCE STATEMENT Place-cell activity in the hippocampal CA1 area is not stable even in a familiar environment, but changes dynamically over time. However, the mechanism behind these changes is unknown. Using in vivo calcium imaging, activity of CA1 neurons were tracked during multiple sessions with variable intervals. The overlap rate of the active place-cell population was constant regardless of the number of tasks within a fixed time. Furthermore, the dynamics were suppressed by an NMDA receptor antagonist. This NMDA receptor-dependent, continuous change in the place-cell activity may encode temporal information of episodes.

Precise spike timing dynamics of hippocampal place cell activity sensitive to cholinergic disruption.

New memory formation depends on both the hippocampus and modulatory effects of acetylcholine. The mechanism by which acetylcholine levels in the hippocampus enable new encoding remains poorly understood. Here, we tested the hypothesis that cholinergic modulation supports memory formation by leading to structured spike timing in the hippocampus. Specifically, we tested if phase precession in dorsal CA1 was reduced under the influence of a systemic cholinergic antagonist. Unit and field potential were recorded from the dorsal CA1 of rats as they completed laps on a circular track for food rewards before and during the influence of the systemically administered acetylcholine muscarinic receptor antagonist scopolamine. We found that scopolamine significantly reduced phase precession of spiking relative to the field theta, and that this was due to a decrease in the frequency of the spiking rhythmicity. We also found that the correlation between position and theta phase was significantly reduced. This effect was not due to changes in spatial tuning as tuning remained stable for those cells analyzed. Similarly, it was not due to changes in lap-to-lap reliability of spiking onset or offset relative to either position or phase as the reliability did not decrease following scopolamine administration. These findings support the hypothesis that memory impairments that follow muscarinic blockade are the result of degraded spike timing in the hippocampus.