Rapid-Eye Movement (REM) sleep correlates with neuronal activity in the brainstem, basal forebrain and lateral hypothalamus (LH). LH melanin-concentrating hormone (MCH)-expressing neurons are active during sleep, however, their action on REM sleep remains unclear. Using optogenetic tools in newly-generated Tg(Pmch-Cre) mice, we found that acute activation of MCH neurons (ChETA, SSFO) at the onset of REM sleep extended the duration of REM, but not non-REM sleep episode. In contrast, their acute silencing (eNpHR3.0, ArchT) reduced the frequency and amplitude of hippocampal theta rhythm, without affecting REM sleep duration. In vitro activation of MCH neuron terminals induced GABAA-mediated inhibitory post-synaptic currents (IPSCs) in wake-promoting histaminergic neurons of the tuberomammillary nucleus (TMN), while in vivo activation of MCH neuron terminals in TMN or medial septum also prolonged REM sleep episodes. Collectively, these results suggest that activation of MCH neurons maintains REM sleep, possibly through inhibition of arousal circuits in the mammalian brain.

Reward-seeking behavior is regulated by a diverse collection of inputs to the nucleus accumbens (NAc). The information encoded in each excitatory afferent to the NAc is unknown, in part because it is unclear when these pathways are active in relation to behavior. Here we compare the activity profiles of amygdala, hippocampal, and thalamic inputs to the NAc shell in mice performing a cued reward-seeking task using GCaMP-based fiber photometry. We find that the rostral and caudal ends of the NAc shell are innervated by distinct but intermingled populations of forebrain neurons that exhibit divergent feeding-related activity. In the rostral NAc shell, a coordinated network-wide reduction in excitatory drive correlates with feeding, and reduced input from individual pathways is sufficient to promote it. Overall, the data suggest that pathway-specific input activity at a population level may vary more across the NAc than between pathways.

BackgroundThalamocortical EEG rhythms in gamma (30-80 Hz) and high-gamma (80-200 Hz) ranges have been linked to arousal and conscious processes. To test the hypothesis that general anesthetics attenuate these rhythms, we characterized the concentration-effect relationship of propofol on the spectral power of these rhythms. In view of the ongoing debate about cortex versus thalamus as the primary site of anesthetic action for unconsciousness, we also compared the relative sensitivity of cortex and thalamus to this effect propofol.MethodsAdult male Long-Evans rats were chronically implanted with electrodes in somatosensory (barrel) cortex and ventroposteromedial thalamus. Propofol was delivered by a computer-controlled infusion using real-time pharmacokinetic modeling to obtain the desired plasma concentration. Spectral power was assessed during baseline, at four stable propofol plasma-concentrations (0, 3,6,9,12 μg/ml) and during recovery over four frequency ranges (30-50, 51-75, 76-125, 126-200 Hz). Unconsciousness was defined as complete loss of righting reflex. Multiple regression was used to model the change of power (after logarithmic transformation) as a function of propofol concentration and recording site.ResultsUnconsciousness occurred at the 9 μg/ml concentration in all animals. Propofol caused a robust linear concentration-dependent attenuation of cortical power in the 76-200 Hz range and of thalamic power in the 51-200 Hz range. In all instances the concentration-effect slope for the thalamus was markedly steeper than for the cortex. Furthermore the lowest concentration causing unconsciousness significantly reduced cortical power in the 126-200 Hz range and thalamic power in the 51-200 Hz range.ConclusionsPropofol causes a concentration-dependent attenuation of the power of thalamocortical rhythms in the 51-200 Hz range and this effect is far more pronounced for the thalamus, where the attenuation provides a robust correlate of the hypnotic action of propofol.

We conclude that induction of anesthesia with propofol in these patients was associated with concurrent alterations of cortical and sensory thalamic activity.

Isoflurane causes a concentration-dependent attenuation of the power of thalamocortical rhythms in the 30 to 200 Hz range, and this effect is more pronounced for the thalamus than for the cortex for frequencies >50 Hz. In comparison with propofol, isoflurane caused a greater attenuation in the cortex, but the effects on the thalamus were similar. Isoflurane and propofol cause common alterations of fast thalamocortical rhythms that may constitute an electrophysiologic signature of the anesthetized state.

We conclude that partial antagonism of propofol anaesthesia by physostigmine is associated with an increase in thalamic activity reflected in gamma/high-gamma (50-200 Hz) power. These findings are consistent with the view that anaesthetic-induced unconsciousness is associated with impairment of thalamic function.

Synaptic plasticity in olfactory inputs to the lateral entorhinal cortex may result in lasting changes in the processing of olfactory stimuli. Changes in dopaminergic tone can have strong effects on basal evoked synaptic responses in the superficial layers of the entorhinal cortex, and the current study investigated whether dopamine may modulate the induction of long-term potentiation (LTP) and depression (LTD) in piriform cortex inputs to layer II of the lateral entorhinal cortex in awake rats. Groups of animals were pretreated with either saline or the selective dopamine reuptake inhibitor GBR12909 prior to low or high frequency stimulation to induce LTD or LTP. In saline-treated groups, synaptic responses were potentiated to 122.4+/-6.4% of baseline levels following LTP induction, and were reduced to 84.5+/-4.9% following induction of LTD. Changes in synaptic responses were maintained for up to 60min and returned to baseline levels within 24h. In contrast, induction of both LTP and LTD was blocked in rats pretreated with GBR12909. Dopaminergic suppression of synaptic plasticity in the entorhinal cortex may serve to restrain activity-dependent plasticity during reward-relevant behavioral states or during processing of novel stimuli.

There have been significant advances in the treatment of psychiatric disease in the last half century, but it is still unclear which neural circuits are ultimately responsible for specific disease states. Fortunately, technical limitations that have constrained this research have recently been mitigated by advances in research tools that facilitate circuit-based analyses. The most prominent of these tools is optogenetics, which refers to the use of genetically encoded, light-sensitive proteins that can be used to manipulate discrete neural circuits with temporal precision. Optogenetics has recently been used to examine the neural underpinnings of both psychiatric disease and symptom relief, and this research has rapidly identified novel therapeutic targets for what could be a new generation of rational drug development. As these and related methodologies for controlling neurons ultimately make their way into the clinic, circuit-based strategies for alleviating psychiatric symptoms could become a remarkably refined approach to disease treatment.