Thomas J. McHugh

Updating hippocampal representations: CA2 joins the circuit.

The hippocampus integrates the encoding, storage and recall of memories, binding the spatio-temporal and sensory information that constitutes experience and keeping episodes in their correct context. The rapid and accurate processing of such daunting volumes of continuously changing data relies on dynamically assigning different aspects of mnemonic processing to specialized, interconnected networks corresponding to the anatomical subfields of dentate gyrus (DG), CA3 and CA1. However, differentially processed information ultimately has to be reintegrated into conjunctive representations, and this is unlikely to be achieved by unidirectional, sequential steps through a DG-CA3-CA1 loop. In this Review, we highlight recently discovered anatomical and physiological features that are likely to necessitate updates to the hippocampal circuit diagram, particularly by incorporating the oft-neglected CA2 region.

The Synchronous Activity of Lateral Habenular Neurons Is Essential for Regulating Hippocampal Theta Oscillation

Lateral habenula (LHb) has attracted growing interest as a regulator of serotonergic and dopaminergic neurons in the CNS. However, it remains unclear how the LHb modulates brain states in animals. To identify the neural substrates that are under the influence of LHb regulation, we examined the effects of rat LHb lesions on the hippocampal oscillatory activity associated with the transition of brain states. Our results showed that the LHb lesion shortened the theta activity duration both in anesthetized and sleeping rats. Furthermore, this inhibitory effect of LHb lesion on theta maintenance depended upon an intact serotonergic median raphe, suggesting that LHb activity plays an essential role in maintaining hippocampal theta oscillation via the serotonergic raphe. Multiunit recording of sleeping rats further revealed that firing of LHb neurons showed significant phase-locking activity at each theta oscillation cycle in the hippocampus. LHb neurons showing activity that was coordinated with that of the hippocampal theta were localized in the medial LHb division, which receives afferents from the diagonal band of Broca (DBB), a pacemaker region for the hippocampal theta oscillation. Thus, our findings indicate that the DBB may pace not only the hippocampus, but also the LHb, during rapid eye movement sleep. Since serotonin is known to negatively regulate theta oscillation in the hippocampus, phase-locking activity of the LHb neurons may act, under the influence of the DBB, to maintain the hippocampal theta oscillation by modulating the activity of serotonergic neurons.

Near-infrared deep brain stimulation via upconversion nanoparticle–mediated optogenetics

Stimulating deep inside the brain Noninvasive deep brain stimulation is an important goal in neuroscience and neuroengineering. Optogenetics normally requires the use of a blue laser inserted into the brain. Chen et al. used specialized nanoparticles that can upconvert near-infrared light from outside the brain into the local emission of blue light (see the Perspective by Feliu et al.). They injected these nanoparticles into the ventral tegmental area of the mouse brain and activated channelrhodopsin expressed in dopaminergic neurons with near-infrared light generated outside the skull at a distance of several millimeters. This technique allowed distant near-infrared light to evoke fast increases in dopamine release. The method was also used successfully to evoke fear memories in the dentate gyrus during fear conditioning. Science, this issue p. 679; see also p. 633 Optogenetic experiments can be performed inside the mouse brain by using near-infrared light applied outside the skull. Optogenetics has revolutionized the experimental interrogation of neural circuits and holds promise for the treatment of neurological disorders. It is limited, however, because visible light cannot penetrate deep inside brain tissue. Upconversion nanoparticles (UCNPs) absorb tissue-penetrating near-infrared (NIR) light and emit wavelength-specific visible light. Here, we demonstrate that molecularly tailored UCNPs can serve as optogenetic actuators of transcranial NIR light to stimulate deep brain neurons. Transcranial NIR UCNP-mediated optogenetics evoked dopamine release from genetically tagged neurons in the ventral tegmental area, induced brain oscillations through activation of inhibitory neurons in the medial septum, silenced seizure by inhibition of hippocampal excitatory cells, and triggered memory recall. UCNP technology will enable less-invasive optical neuronal activity manipulation with the potential for remote therapy.

The Hippocampal CA2 Ensemble Is Sensitive to Contextual Change

Contextual learning involves associating cues with an environment and relating them to past experience. Previous data indicate functional specialization within the hippocampal circuit: the dentate gyrus (DG) is crucial for discriminating similar contexts, whereas CA3 is required for associative encoding and recall. Here, we used Arc/H1a catFISH imaging to address the contribution of the largely overlooked CA2 region to contextual learning by comparing ensemble codes across CA3, CA2, and CA1 in mice exposed to familiar, altered, and novel contexts. Further, to manipulate the quality of information arriving in CA2 we used two hippocampal mutant mouse lines, CA3-NR1 KOs and DG-NR1 KOs, that result in hippocampal CA3 neuronal activity that is uncoupled from the animals sensory environment. Our data reveal largely coherent responses across the CA axis in control mice in purely novel or familiar contexts; however, in the mutant mice subject to these protocols the CA2 response becomes uncoupled from CA1 and CA3. Moreover, we show in wild-type mice that the CA2 ensemble is more sensitive than CA1 and CA3 to small changes in overall context. Our data suggest that CA2 may be tuned to remap in response to any conflict between stored and current experience.

Phasic reward responses in the monkey striatum as detected by voltammetry with diamond microelectrodes

Reward-induced burst firing of dopaminergic neurons has mainly been studied in the primate midbrain. Voltammetry allows high-speed detection of dopamine release in the projection area. Although voltammetry has revealed presynaptic modulation of dopamine release in the striatum, to date, reward-induced release in awakened brains has been recorded only in rodents. To make such recordings, it is possible to use conventional carbon fibres in monkey brains but the use of these fibres is limited by their physical fragility. In this study, constant-potential amperometry was applied to novel diamond microelectrodes for high-speed detection of dopamine. In primate brains during Pavlovian cue-reward trials, a sharp response to a reward cue was detected in the caudate of Japanese monkeys. Overall, this method allows measurements of monoamine release in specific target areas of large brains, the findings from which will expand the knowledge of reward responses obtained by unit recordings.

Top-down cortical input during NREM sleep consolidates perceptual memory

Perceptual memory needs slow-wave sleep We know little about the mechanisms by which the brain consolidates nondeclarative (perceptual) memories. In a series of behavioral, optogenetic, and electrophysiological experiments, Miyamoto et al. show that coordinated neuronal information flow during sleep is required for perceptual memory formation. Activity spreading from the secondary motor area (brain area M2) to the primary sensory region S1 is necessary for this particular kind of memory consolidation. Disturbing this coordinated input during slow-wave sleep immediately after memory acquisition prevented mice from learning a simple texture discrimination task. Science, this issue p. 1315 Perceptual memory consolidation needs temporal coordination of neurons in brain areas M2 and S1 during slow-wave sleep. During tactile perception, long-range intracortical top-down axonal projections are essential for processing sensory information. Whether these projections regulate sleep-dependent long-term memory consolidation is unknown. We altered top-down inputs from higher-order cortex to sensory cortex during sleep and examined the consolidation of memories acquired earlier during awake texture perception. Mice learned novel textures and consolidated them during sleep. Within the first hour of non–rapid eye movement (NREM) sleep, optogenetic inhibition of top-down projecting axons from secondary motor cortex (M2) to primary somatosensory cortex (S1) impaired sleep-dependent reactivation of S1 neurons and memory consolidation. In NREM sleep and sleep-deprivation states, closed-loop asynchronous or synchronous M2-S1 coactivation, respectively, reduced or prolonged memory retention. Top-down cortical information flow in NREM sleep is thus required for perceptual memory consolidation.

Silencing CA3 disrupts temporal coding in the CA1 ensemble

In addition to the place-cell rate code, hippocampal area CA1 employs a temporal code, both on the single-cell and ensemble level, to accurately represent space. Although there is clear evidence that this precise spike timing is organized by theta and gamma oscillations that are present in hippocampus, the circuit mechanisms underlying these temporal codes remain poorly understood. We found that the loss of CA3 input abolished temporal coding at the ensemble level in CA1 despite the persistence of both rate and temporal coding in individual neurons. Moreover, low gamma oscillations were present in CA1 despite the absence of CA3 input, but spikes associated with these periods carried significantly reduced spatial information. Our findings dissociate temporal coding at the single-cell (phase precession) and population (theta sequences) levels and suggest that CA3 input is crucial for temporal coordination of the CA1 ensemble code for space.

Backpropagating Action Potentials Enable Detection of Extrasynaptic Glutamate by NMDA Receptors

Summary Synaptic NMDA receptors (NMDARs) are crucial for neural coding and plasticity. However, little is known about the adaptive function of extrasynaptic NMDARs occurring mainly on dendritic shafts. Here, we find that in CA1 pyramidal neurons, backpropagating action potentials (bAPs) recruit shaft NMDARs exposed to ambient glutamate. In contrast, spine NMDARs are “protected,” under baseline conditions, from such glutamate influences by perisynaptic transporters: we detect bAP-evoked Ca2+ entry through these receptors upon local synaptic or photolytic glutamate release. During theta-burst firing, NMDAR-dependent Ca2+ entry either downregulates or upregulates an h-channel conductance (Gh) of the cell depending on whether synaptic glutamate release is intact or blocked. Thus, the balance between activation of synaptic and extrasynaptic NMDARs can determine the sign of Gh plasticity. Gh plasticity in turn regulates dendritic input probed by local glutamate uncaging. These results uncover a metaplasticity mechanism potentially important for neural coding and memory formation.

Retrograde Synaptic Signaling Mediated by K+ Efflux through Postsynaptic NMDA Receptors

Synaptic NMDA receptors (NMDARs) carry inward Ca(2+) current responsible for postsynaptic signaling and plasticity in dendritic spines. Whether the concurrent K(+) efflux through the same receptors into the synaptic cleft has a physiological role is not known. Here, we report that NMDAR-dependent K(+) efflux can provide a retrograde signal in the synapse. In hippocampal CA3-CA1 synapses, the bulk of astrocytic K(+) current triggered by synaptic activity reflected K(+) efflux through local postsynaptic NMDARs. The local extracellular K(+) rise produced by activation of postsynaptic NMDARs boosted action potential-evoked presynaptic Ca(2+) transients and neurotransmitter release from Schaffer collaterals. Our findings indicate that postsynaptic NMDAR-mediated K(+) efflux contributes to use-dependent synaptic facilitation, thus revealing a fundamental form of retrograde synaptic signaling.

Distinct preoptic-BST nuclei dissociate paternal and infanticidal behavior in mice.

Paternal behavior is not innate but arises through social experience. After mating and becoming fathers, male mice change their behavior toward pups from infanticide to paternal care. However, the precise brain areas and circuit mechanisms connecting these social behaviors are largely unknown. Here we demonstrated that the c‐Fos expression pattern in the four nuclei of the preoptic‐bed nuclei of stria terminalis (BST) region could robustly discriminate five kinds of previous social behavior of male mice (parenting, infanticide, mating, inter‐male aggression, solitary control). Specifically, neuronal activation in the central part of the medial preoptic area (cMPOA) and rhomboid nucleus of the BST (BSTrh) retroactively detected paternal and infanticidal motivation with more than 95% accuracy. Moreover, cMPOA lesions switched behavior in fathers from paternal to infanticidal, while BSTrh lesions inhibited infanticide in virgin males. The projections from cMPOA to BSTrh were largely GABAergic. Optogenetic or pharmacogenetic activation of cMPOA attenuated infanticide in virgin males. Taken together, this study identifies the preoptic‐BST nuclei underlying social motivations in male mice and reveals unexpected complexity in the circuit connecting these nuclei.