Synaptic Homeostasis and Restructuring across the Sleep-Wake Cycle.

Sleep is critical for hippocampus-dependent memory consolidation. However, the underlying mechanisms of synaptic plasticity are poorly understood. The central controversy is on whether long-term potentiation (LTP) takes a role during sleep and which would be its specific effect on memory. To address this question, we used immunohistochemistry to measure phosphorylation of Ca2+/calmodulin-dependent protein kinase II (pCaMKIIα) in the rat hippocampus immediately after specific sleep-wake states were interrupted. Control animals not exposed to novel objects during waking (WK) showed stable pCaMKIIα levels across the sleep-wake cycle, but animals exposed to novel objects showed a decrease during subsequent slow-wave sleep (SWS) followed by a rebound during rapid-eye-movement sleep (REM). The levels of pCaMKIIα during REM were proportional to cortical spindles near SWS/REM transitions. Based on these results, we modeled sleep-dependent LTP on a network of fully connected excitatory neurons fed with spikes recorded from the rat hippocampus across WK, SWS and REM. Sleep without LTP orderly rescaled synaptic weights to a narrow range of intermediate values. In contrast, LTP triggered near the SWS/REM transition led to marked swaps in synaptic weight ranking. To better understand the interaction between rescaling and restructuring during sleep, we implemented synaptic homeostasis and embossing in a detailed hippocampal-cortical model with both excitatory and inhibitory neurons. Synaptic homeostasis was implemented by weakening potentiation and strengthening depression, while synaptic embossing was simulated by evoking LTP on selected synapses. We observed that synaptic homeostasis facilitates controlled synaptic restructuring. The results imply a mechanism for a cognitive synergy between SWS and REM, and suggest that LTP at the SWS/REM transition critically influences the effect of sleep: Its lack determines synaptic homeostasis, its presence causes synaptic restructuring.

5-MeO-DMT induces sleep-like LFP spectral signatures in the hippocampus and prefrontal cortex of awake rats.

5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a potent classical psychedelic known to induce changes in locomotion, behaviour, and sleep in rodents. However, there is limited knowledge regarding its acute neurophysiological effects. Local field potentials (LFPs) are commonly used as a proxy for neural activity, but previous studies investigating psychedelics have been hindered by confounding effects of behavioural changes and anaesthesia, which alter these signals. To address this gap, we investigated acute LFP changes in the hippocampus (HP) and medial prefrontal cortex (mPFC) of freely behaving rats, following 5-MeO-DMT administration. 5-MeO-DMT led to an increase of delta power and a decrease of theta power in the HP LFPs, which could not be accounted for by changes in locomotion. Furthermore, we observed a dose-dependent reduction in slow (20-50 Hz) and mid (50-100 Hz) gamma power, as well as in theta phase modulation, even after controlling for the effects of speed and theta power. State map analysis of the spectral profile of waking behaviour induced by 5-MeO-DMT revealed similarities to electrophysiological states observed during slow-wave sleep (SWS) and rapid-eye-movement (REM) sleep. Our findings suggest that the psychoactive effects of classical psychedelics are associated with the integration of waking behaviours with sleep-like spectral patterns in LFPs.

Dopamine Modulates Delta-Gamma Phase-Amplitude Coupling in the Prefrontal Cortex of Behaving Rats.

Dopamine release and phase-amplitude cross-frequency coupling (CFC) have independently been implicated in prefrontal cortex (PFC) functioning. To causally investigate whether dopamine release affects phase-amplitude comodulation between different frequencies in local field potentials (LFP) recorded from the medial PFC (mPFC) of behaving rats, we used RuBiDopa, a light-sensitive caged compound that releases the neurotransmitter dopamine when irradiated with visible light. LFP power did not change in any frequency band after the application of light-uncaged dopamine, but significantly strengthened phase-amplitude comodulation between delta and gamma oscillations. Saline did not exert significant changes, while injections of dopamine and RuBiDopa produced a slow increase in comodulation for several minutes after the injection. The results show that dopamine release in the medial PFC shifts phase-amplitude comodulation from theta-gamma to delta-gamma. Although being preliminary results due to the limitation of the low number of animals present in this study, our findings suggest that dopamine-mediated modification of the frequencies involved in comodulation could be a mechanism by which this neurotransmitter regulates functioning in mPFC.