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The N -methyl- d -aspartate receptor (NMDAR) antagonist ketamine has attracted enormous interest in mental health research owing to its rapid antidepressant actions, but its mechanism of action has remained elusive. Here we show that blockade of NMDAR-dependent bursting activity in the ‘anti-reward center’, the lateral habenula (LHb), mediates the rapid antidepressant actions of ketamine in rat and mouse models of depression. LHb neurons show a significant increase in burst activity and theta-band synchronization in depressive-like animals, which is reversed by ketamine. Burst-evoking photostimulation of LHb drives behavioural despair and anhedonia. Pharmacology and modelling experiments reveal that LHb bursting requires both NMDARs and low-voltage-sensitive T-type calcium channels (T-VSCCs). Furthermore, local blockade of NMDAR or T-VSCCs in the LHb is sufficient to induce rapid antidepressant effects. Our results suggest a simple model whereby ketamine quickly elevates mood by blocking NMDAR-dependent bursting activity of LHb neurons to disinhibit downstream monoaminergic reward centres, and provide a framework for developing new rapid-acting antidepressants. The rapid antidepressant activity of ketamine results from reversal of increased burst firing and synchronization in the lateral habenula in rat and mouse models of depression. A burst of activity for antidepressants The lateral habenula (LHb) is a region of the brain that is associated with aversion and other negative emotions. Hailan Hu and colleagues present a pair of papers in this week's issue on the role of burst firing in LHb neurons in depression in rats. First, they show that ketamine, a drug that can be used as an antidepressant, blocks LHb neuron bursting activity, and that both NMDAR and low-voltage-sensitive T-type calcium channels (T-VSCCs) are required for the drug to be effective. In the second study, the authors identify a potential mechanism for regulating this bursting behaviour that could represent a new therapeutic target. Levels of an astroglial potassium channel, Kir4.1, covary with the degree of membrane hyperpolarization and bursting activity of LHb neurons, as well as depression-related behaviours in various rodent models. The team suggest that blocking LHb neuron bursting activity could revive reward centres in the brain and elevate mood, and provide a model framework for developing rapid-acting antidepressants.

The authors find that optogenetic stimulation of melanin-concentrating hormone (MCH)-expressing neurons in the lateral hypothalamus selectively extends the duration of paradoxical sleep episodes in mice. Activation of MCH fibers in the tuberomammillary nucleus leads to the release of GABA and a similar increase in paradoxical sleep stability. Rapid-eye movement (REM) sleep correlates with neuronal activity in the brainstem, basal forebrain and lateral hypothalamus. Lateral hypothalamus melanin-concentrating hormone (MCH)-expressing neurons are active during sleep, but their effects on REM sleep remain 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 episodes. In contrast, their acute silencing (eNpHR3.0, archaerhodopsin) reduced the frequency and amplitude of hippocampal theta rhythm without affecting REM sleep duration. In vitro activation of MCH neuron terminals induced GABA A -mediated inhibitory postsynaptic currents in wake-promoting histaminergic neurons of the tuberomammillary nucleus (TMN), and 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.

Wang and colleagues find that weakening hippocampal theta in a familiar environment reduces the performance of rats in a spatial memory task, decreases the number of theta sequences and degrades internally generated hippocampal episode cell firing, while leaving place cell firing intact. The same weakening of theta also prevents the formation of a precise spatial representation in a novel environment unless proximal cues are present. Together these results suggest that the mechanisms underlying internally generated hippocampal sequences of activity are crucial for episodic memory. Sensory cue inputs and memory-related internal brain activities govern the firing of hippocampal neurons, but which specific firing patterns are induced by either of the two processes remains unclear. We found that sensory cues guided the firing of neurons in rats on a timescale of seconds and supported the formation of spatial firing fields. Independently of the sensory inputs, the memory-related network activity coordinated the firing of neurons not only on a second-long timescale, but also on a millisecond-long timescale, and was dependent on medial septum inputs. We propose a network mechanism that might coordinate this internally generated firing. Overall, we suggest that two independent mechanisms support the formation of spatial firing fields in hippocampus, but only the internally organized system supports short-timescale sequential firing and episodic memory.

Theta and gamma rhythms and their cross-frequency coupling play critical roles in perception, attention, learning, and memory. Available data suggest that forebrain acetylcholine (ACh) signaling promotes theta-gamma coupling, although the mechanism has not been identified. Recent evidence suggests that cholinergic signaling is both temporally and spatially constrained, in contrast to the traditional notion of slow, spatially homogeneous, and diffuse neuromodulation. Here, we find that spatially constrained cholinergic stimulation can generate theta-modulated gamma rhythms. Using biophysically-based excitatory-inhibitory (E-I) neural network models, we simulate the effects of ACh on neural excitability by varying the conductance of a muscarinic receptor-regulated K + current. In E-I networks with local excitatory connectivity and global inhibitory connectivity, we demonstrate that theta-gamma-coupled firing patterns emerge in ACh modulated network regions. Stable gamma-modulated firing arises within regions with high ACh signaling, while theta or mixed theta-gamma activity occurs at the peripheries of these regions. High gamma activity also alternates between different high-ACh regions, at theta frequency. Our results are the first to indicate a causal role for spatially heterogenous ACh signaling in the emergence of localized theta-gamma rhythmicity. Our findings also provide novel insights into mechanisms by which ACh signaling supports the brain region-specific attentional processing of sensory information.

Grid cells recorded in the medial entorhinal cortex of freely moving rats exhibit firing at regular spatial locations and temporal modulation with theta rhythm oscillations (4 to 11 hertz). We analyzed grid cell spatial coding during reduction of network theta rhythm oscillations caused by medial septum (MS) inactivation with muscimol. During MS inactivation, grid cells lost their spatial periodicity, whereas head-direction cells maintained their selectivity. Conjunctive grid—by—head-direction cells lost grid cell spatial periodicity but retained head-direction specificity. All cells showed reduced rhythmicity in autocorrelations and cross-correlations. This supports the hypothesis that spatial coding by grid cells requires theta oscillations, and dissociates the mechanisms underlying the generation of entorhinal grid cell periodicity and head-direction selectivity.

Accumulation of amyloid β oligomers (AβO) in Alzheimer’s disease (AD) impairs hippocampal theta and gamma oscillations. These oscillations are important in memory functions and depend on distinct subtypes of hippocampal interneurons such as somatostatin-positive (SST) and parvalbumin-positive (PV) interneurons. Here, we investigated whether AβO causes dysfunctions in SST and PV interneurons by optogenetically manipulating them during theta and gamma oscillations in vivo in AβO-injected SST-Cre or PV-Cre mice. Hippocampal in vivo multi-electrode recordings revealed that optogenetic activation of channelrhodopsin-2 (ChR2)-expressing SST and PV interneurons in AβO-injected mice selectively restored AβO-induced reduction of the peak power of theta and gamma oscillations, respectively, and resynchronized CA1 pyramidal cell (PC) spikes. Moreover, SST and PV interneuron spike phases were resynchronized relative to theta and gamma oscillations, respectively. Whole-cell voltage-clamp recordings in CA1 PC in ex vivo hippocampal slices from AβO-injected mice revealed that optogenetic activation of SST and PV interneurons enhanced spontaneous inhibitory postsynaptic currents (IPSCs) selectively at theta and gamma frequencies, respectively. Furthermore, analyses of the stimulus–response curve, paired-pulse ratio, and short-term plasticity of SST and PV interneuron-evoked IPSCs ex vivo showed that AβO increased the initial GABA release probability to depress SST/PV interneuron’s inhibitory input to CA1 PC selectively at theta and gamma frequencies, respectively. Our results reveal frequency-specific and interneuron subtype-specific presynaptic dysfunctions of SST and PV interneurons’ input to CA1 PC as the synaptic mechanisms underlying AβO-induced impairments of hippocampal network oscillations and identify them as potential therapeutic targets for restoring hippocampal network oscillations in early AD.

Worrying about perceived threats is a hallmark of multiple psychological disorders including anxiety. This concern about future events is particularly important when an individual is faced with an approach-avoidance conflict. Potential goals to approach are known to be represented in the dorsal hippocampus during theta cycles. Similarly, important information that is distant from the animal’s position is represented during hippocampal high-synchrony events (HSEs), which coincide with sharp-wave ripples (SWRs). It is likely that potential future threats may be similarly represented. We examined how threats and rewards were represented within the hippocampus during approach-avoidance conflicts in rats faced with a predator-like robot guarding a food reward. We found decoding of the pseudo-predator’s location during HSEs when hesitating in the nest and during theta prior to retreating as the rats approached the pseudo-predator. After the first attack, we observed new place fields appearing at the location of the robot (not the location the rat was when attacked). The anxiolytic diazepam reduced anxiety-like behavior and altered hippocampal local field potentials (LFPs), including reducing SWRs, suggesting that one potential mechanism of diazepam’s actions may be through altered representations of imagined threat. These results suggest that hippocampal representation of potential threats could be an important mechanism that underlies worry and a potential target for anxiolytics.

Rhythmic synchronizations of hippocampus (HC) and prefrontal cortex (PFC) at theta frequencies (4–8 Hz) are thought to mediate key cognitive functions, and disruptions of HC-PFC coupling were implicated in psychiatric diseases. Theta coupling is thought to represent a HC-to-PFC drive transmitted via the well-described unidirectional HC projection to PFC. In comparison, communication in the PFC-to-HC direction is less understood, partly because no known direct anatomical connection exists. Two recent findings, i.e., reciprocal projections between the thalamic nucleus reuniens (nRE) with both PFC and HC and a unique 2–5 Hz rhythm reported in the PFC, indicate, however, that a second low-frequency oscillation may provide a synchronizing signal from PFC to HC via nRE. Thus, in this study, we recorded local field potentials in the PFC, HC, and nRE to investigate the role of nRE in PFC–HC coupling established by the two low-frequency oscillations. Using urethane-anesthetized rats and stimulation of pontine reticular formation to experimentally control the parameters of both forebrain rhythms, we found that theta and 2–5 Hz rhythm were dominant in HC and PFC, respectively, but were present and correlated in all three signals. Removal of nRE influence, either statistically (by partialization of PFC–HC correlation when controlling for the nRE signal) or pharmacologically (by lidocaine microinjection in nRE), resulted in decreased coherence between the PFC and HC 2–5-Hz oscillations, but had minimal effect on theta coupling. This study proposes a novel thalamo-cortical network by which PFC-to-HC coupling occurs via a 2–5 Hz oscillation and is mediated through the nRe.

Researchers are discovering how the ingredients in a cup of tea can lift mood, improve focus and perhaps even ward off depression and dementia. Researchers are discovering how the ingredients in a cup of tea can lift mood, improve focus and perhaps even ward off depression and dementia.

Background Depression is a prevalent mental disorder, and prolonged exposure to social defeat is a major contributing factor in the onset of depression. Repeated social defeat stress (RSDS) is a commonly used animal model for depression, significantly impacting on the pathogenesis of depression-related to social disorders. The basolateral amygdala (BLA) and the ventral hippocampus (vHPC) are critical brain regions involved in RSDS-induced social behavioral disorders, but the specific neural oscillations occurring in these regions following social defeat remain unclear. Methods Using simultaneous multi-electrode recordings, we captured local field potentials (LFPs) from BLA and vHPC while the stressed mice underwent a social interaction test. Power spectral analysis and Amplitude transform entropy were respectively applied to assess social defeat–induced alterations in neural oscillatory activity and directional inter-regional communication. Results Our study demonstrated that repeated social defeat induces social avoidance and depression-like behaviors. Notably, the power spectral analysis within the BLA and vHPC revealed statistically differences in the theta band (4–12 Hz) between control and RSDS groups, particularly during the With CD1 phase in the 0–3 s stage, when mice entered the social interaction zone, compared to the − 3 –0 s stage prior to enter the zone. Moreover, machine learning analysis successfully classified control and RSDS groups based on neural oscillatory activity in the BLA and vHPC. Finally, ketamine treatment was found to reduce social avoidance and depressive-like behaviors, as well as enhance theta oscillation in the BLA and vHPC. Conclusion These results suggest that social defeat alters theta oscillations in the BLA and vHPC, highlighting potential therapeutic avenues for addressing depression-related social dysfunction.