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Dynamic interactions between the subregions of the hippocampus are required for the encoding and consolidation of memory. While the interplay and contributions of the CA1 and CA3 regions are well understood, we continue to learn more about how CA2 differentially contributes to the organization of network function. For example, CA2 place cells have been reported to be less spatially tuned during exploration, but uniquely capable of coding place while an animal stops. Here we applied chemogenetics to transiently silence CA2 pyramidal cells and found that CA2 influences hippocampal dynamics in a state‐dependent manner. We find that during rest, CA2 inhibition reduces synchronization across regions (CA1, CA2, CA3) and frequency bands (low‐gamma‐ and ripple‐band). Moreover, during new learning CA1 place field formation is slower in the absence of CA2 transmission and during pausing, CA1 pyramidal cells are less excitable without CA2 drive. On the network level, a novel convolutional neural network (SpikeDecoder) was employed to show subregion and state‐dependent changes in spatial coding that agree with our observations on the single cell level. Together these data suggest additional novel roles for CA2 in governing and differentiating hippocampal dynamics under discrete behavioral states. [ABSTRACT FROM AUTHOR]

Social animals become stressed upon social isolation, proactively engaging in affiliative contacts among conspecifics after resocialization. We have previously reported that calcitonin receptor (Calcr) expressing neurons in the central part of the medial preoptic area (cMPOA) mediate contact-seeking behaviors in female mice. Calcr neurons in the posterodorsal part of the medial amygdala (MeApd) are also activated by resocialization, however their role in social affiliation is still unclear. Here we first investigated the functional characteristics of MeApd Calcr + cells; these neurons are GABAergic and show female-biased Calcr expression. Next, using an adeno-associated virus vector expressing a short hairpin RNA targeting Calcr we aimed to identify its molecular role in the MeApd. Inhibiting Calcr expression in the MeApd increased social contacts during resocialization without affecting locomotor activity, suggesting that the endogenous Calcr signaling in the MeApd suppresses social contacts. These results demonstrate the distinct roles of Calcr in the cMPOA and MeApd for regulating social affiliation. [ABSTRACT FROM AUTHOR]

Hippocampal function is severely compromised by prolonged, uncontrollable stress. However, how stress alters neural representations of our surroundings and events that occur within them remains less clear. We review hippocampal place cell studies that examine how spatial coding is affected by acute and chronic stress, as well as by stress accompanying fear conditioning. Emerging data suggest that chronic stress disrupts the acuity and specificity of CA1 spatial coding, both in familiar and novel contexts, and alters hippocampal oscillations. By contrast, acute stress may have a facilitatory impact on spatial representations. These findings encourage a fresh look at the documented stress-induced changes in hippocampal anatomy and in vitro excitability, and offer a new perspective on the links between stress and memory. Chronic stress alters the activity of hippocampal place cells, leading to firing rate changes (rate remapping) in familiar contexts and impaired global remapping between distinct contexts. Acute stress improves the spatial information carried by place cells, making their activity more predictive of the location of an animal in its surroundings, whereas chronic stress decreases it, suggesting that acute and chronic stress have differential impacts on CA1 spatial coding. Associative fear learning induces partial remapping of the place cell map by altering the firing rates and preferred firing locations of a subpopulation of place cells. The remapped place cell population following associative fear learning is preferentially activated during consolidation-associated sharp-wave ripples. Both stress and associative fear alter CA1 neural oscillations during exploratory behavior. [ABSTRACT FROM AUTHOR]

The hippocampal activity of mutant mice exhibiting CA1 restricted deletion of the N-methyl-D-aspartate receptor subunit 1 (NMDAR1) gene was analyzed by utilizing multielectrode recording techniques. The CA1 restricted NMDAR1 mutants exhibited normal neuronal firing activity characterized by rhythmic modulations of the firing rate with a theta frequency of 8-10 Hertz. However, the NMDAR1 mutants exhibited deficient neuronal firing during the performance of spatial tasks indicating the role of NMDAR1 in spatial memory and synaptic plasticity.

Observation of the reoxidation and reduction of the primary electron acceptor in photosystem I revealed that the reduced acceptor, whose decay rate was greater than the formation rate, accumulated at low concentration. The photosystem I reaction center is found in the cells of photosystem II deletion mutant obtained from the cyanobacterium Synechocystis sp. PCC 6803.

Chronic and acute stress differentially affect behavior as well as the structural integrity of the hippocampus, a key brain region involved in cognition and memory. However, it remains unclear if and how the facilitatory effects of acute stress on hippocampal information coding are disrupted as the stress becomes chronic. To examine this, we compared the impact of acute and chronic stress on neural activity in the CA1 subregion of male mice subjected to a chronic immobilization stress (CIS) paradigm. We observed that following first exposure to stress (acute stress), the spatial information encoded in the hippocampus sharpened, and the neurons became increasingly tuned to the underlying theta oscillations in the local field potential (LFP). However, following repeated exposure to the same stress (chronic stress), spatial tuning was poorer and the power of both the slow-gamma (30–50 Hz) and fast-gamma (55–90 Hz) oscillations, which correlate with excitatory inputs into the region, decreased. These results support the idea that acute and chronic stress differentially affect neural computations carried out by hippocampal circuits and suggest that acute stress may improve cognitive processing. [ABSTRACT FROM AUTHOR]

Although Lorente de No' recognized the anatomical distinction of the hippocampal Cornu Ammonis (CA) 2 region, it had, until recently, been assigned no unique function. Its location between the key players of the circuit, CA3 and CA1, which along with the entorhinal cortex and dentate gyrus compose the classic trisynaptic circuit, further distracted research interest. However, the connectivity of CA2 pyramidal cells, together with unique patterns of gene expression, hints at a much larger contribution to hippocampal information processing than has been ascribed. Here we review recent advances that have identified new roles for CA2 in hippocampal centric processing, together with specialized functions in social memory and, potentially, as a broadcaster of novelty. These new data, together with CA2's role in disease, justify a closer look at how this small region exerts its influence and how it might best be exploited to understand and treat disease-related circuit dysfunctions. [ABSTRACT FROM AUTHOR]

Hippocampus receives dense serotonergic input specifically from raphe nuclei. However, what information is carried by this input and its impact on behavior has not been fully elucidated. Here we used in vivo two-photon imaging of activity of hippocampal median raphe projection fibers in behaving male and female mice and identified two distinct populations: one linked to reward delivery and the other to locomotion. Local optogenetic manipulation of these fibers confirmed a functional role for these projections in the modulation of reward-induced behavior. The diverse function of serotonergic inputs suggests a key role in integrating locomotion and reward information into the hippocampal CA1. [ABSTRACT FROM AUTHOR]

Cortical neurons fire intermittently and synchronously during non-rapid eye movement sleep (NREMS), in which active and silent periods are referred to as ON and OFF periods, respectively. Neuronal firing rates during ON periods (NREMS-ON-activity) are similar to those of wakefulness (W-activity), raising the possibility that NREMS-ON neuronal-activity is fragmented W-activity. To test this, we investigated the patterning and organization of cortical spike trains and of spike ensembles in neuronal networks using extracellular recordings in mice. Firing rates of neurons during NREMS-ON and W were similar, but showed enhanced bursting in NREMS with no apparent preference in occurrence, relative to the beginning or end of the on-state. Additionally, there was an overall increase in the randomness of occurrence of sequences comprised of multi-neuron ensembles in NREMS recorded from tetrodes. In association with increased burst firing, somatic calcium transients were increased in NREMS. The increased calcium transients associated with bursting during NREM may activate calcium-dependent, cell-signaling pathways for sleep related cellular processes. [ABSTRACT FROM AUTHOR]

Cargo transport along axons, a physiological process mediated by motor proteins, is essential for neuronal function and survival. A current limitation in the study of axonal transport is the lack of a robust imaging technique with a high spatiotemporal resolution to visualize and quantify the movement of motor proteins in real‐time and in different depth planes. Herein, we present a dynamic imaging technique that fully exploits the characteristics of upconversion nanoparticles. This technique can be used as a microscopic probe for the quantitative in situ tracking of retrograde transport neurons with single‐particle resolution in multilayered cultures. This study may provide a powerful tool to reveal dynamic neuronal activity and intra‐axonal transport function as well as any associated neurodegenerative diseases resulting from mutation or impairment in the axonal transport machinery. [ABSTRACT FROM AUTHOR]

Overcoming aversive emotional memories requires neural systems that detect when fear responses are no longer appropriate so that they can be extinguished. The midbrain ventral tegmental area (VTA) dopamine system has been implicated in reward and more broadly in signaling when a better-than-expected outcome has occurred. This suggests that it may be important in guiding fear to safety transitions. We report that when an expected aversive outcome does not occur, activity in midbrain dopamine neurons is necessary to extinguish behavioral fear responses and engage molecular signaling events in extinction learning circuits. Furthermore, a specific dopamine projection to the nucleus accumbens medial shell is partially responsible for this effect. In contrast, a separate dopamine projection to the medial prefrontal cortex opposes extinction learning. This demonstrates a novel function for the canonical VTA-dopamine reward system and reveals opposing behavioral roles for different dopamine neuron projections in fear extinction learning. [ABSTRACT FROM AUTHOR]

p35 is an activating co-factor of Cyclin-dependent kinase 5 (Cdk5), a protein whose dysfunction has been implicated in a wide-range of neurological disorders including cognitive impairment and disease. Inducible deletion of the p35 gene in adult mice results in profound deficits in hippocampal-dependent spatial learning and synaptic physiology, however the impact of the loss of p35 function on hippocampal in vivo physiology and spatial coding remains unknown. Here, we recorded CA1 pyramidal cell activity in freely behaving p35 cKO and control mice and found that place cells in the mutant mice have elevated firing rates and impaired spatial coding, accompanied by changes in the temporal organization of spiking both during exploration and rest. These data shed light on the role of p35 in maintaining cellular and network excitability and provide a physiological correlate of the spatial learning deficits in these mice. [ABSTRACT FROM AUTHOR]

Emotionally salient information activates orexin neurons in the lateral hypothalamus, leading to increase in sympathetic outflow and vigilance level. How this circuit alters animals' behavior remains unknown. Here we report that noradrenergic neurons in the locus coeruleus (NALC neurons) projecting to the lateral amygdala (LA) receive synaptic input from orexin neurons. Pharmacogenetic/optogenetic silencing of this circuit as well as acute blockade of the orexin receptor-1 (OX1R) decreases conditioned fear responses. In contrast, optogenetic stimulation of this circuit potentiates freezing behavior against a similar but distinct context or cue. Increase of orexinergic tone by fasting also potentiates freezing behavior and LA activity, which are blocked by pharmacological blockade of OX1R in the LC. These findings demonstrate the circuit involving orexin, NALC and LA neurons mediates fear-related behavior and suggests inappropriate excitation of this pathway may cause fear generalization sometimes seen in psychiatric disorders, such as PTSD. [ABSTRACT FROM AUTHOR]

Rapid monoamine release in the dorsal hippocampus is not well characterized, despite its postulated role in modulating fast hippocampal circuit dynamics. We measured monoamine release in the dorsal hippocampus upon stimulation of the ventral tegmental area (VTA) with fast-scan cyclic voltammetry in anesthetized norepinephrine-depleted and non-depleted mice. Within the hippocampus, norepinephrine depletion altered the ability of α 2 adrenergic compounds and transporter blockers to modulate the small, evoked monoamine signal. These manipulations also affected the pH shifts observed after stimulation in a drug-dependent manner. The evoked signal was potentiated by α 2C adrenoceptor subtype antagonism, but was not affected by or α 2A adrenoceptor antagonism. The same subtype-specific pattern was observed on evoked dopamine release in the ventral striatum. The pharmacological and anatomical evidence supports a contribution by dopamine to the VTA-evoked hippocampal monoamine signal, and confirms the interaction between the mesohippocampal and coeruleohippocampal systems. These results also reinforce the notion that α 2C, but not α 2A adrenoceptors regulate endogenous dopaminergic activity. We believe our findings hold implications for understanding the efficacy of α 2 adrenergic agonists and antagonists that are used widely for therapeutic purposes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: To investigate the relationship between neural function and behavior it is necessary to record neuronal activity in the brains of freely behaving animals, a technique that typically involves tethering to a data acquisition system. Optimally this approach allows animals to behave without any interference of movement or task performance. Currently many laboratories in the cognitive and behavioral neuroscience fields employ commercial motorized commutator systems using torque sensors to detect tether movement induced by the trajectory behaviors of animals. Results: In this study we describe a novel motorized commutator system which is automatically controlled by video tracking. To obtain accurate head direction data two light emitting diodes were used and video image noise was minimized by physical light source manipulation. The system calculates the rotation of the animal across a single trial by processing head direction data and the software, which calibrates the motor rotation angle, subsequently generates voltage pulses to actively untwist the tether. This system successfully provides a tether twist-free environment for animals performing behavioral tasks and simultaneous neural activity recording. Conclusions: To the best of our knowledge, it is the first to utilize video tracking generated head direction to detect tether twisting and compensate with a motorized commutator system. Our automatic commutator control system promises an affordable and accessible method to improve behavioral neurophysiology experiments, particularly in mice. [ABSTRACT FROM AUTHOR]

The optogenetic manipulation of light-activated ion-channels/pumps (i.e., opsins) can reversibly activate or suppress neuronal activity with precise temporal control. Therefore, optogenetic techniques hold great potential to establish causal relationships between specific neuronal circuits and their function in freely moving animals. Due to the critical role of the hippocampal CA1 region in memory function, we explored the possibility of targeting an inhibitory opsin, ArchT, to CA1 pyramidal neurons in mice. We established a transgenic mouse line in which tetracycline trans-activator induces ArchT expression. By crossing this line with a CaMKIIα-tTA transgenic line, the delivery of light via an implanted optrode inhibits the activity of excitatory CA1 neurons. We found that light delivery to the hippocampus inhibited the recall of a contextual fear memory. Our results demonstrate that this optogenetic mouse line can be used to investigate the neuronal circuits underlying behavior. [ABSTRACT FROM AUTHOR]

ABSTRACT Stress alters the function of many physiological processes throughout the body, including in the brain. A neural circuit particularly vulnerable to the effects of stress is the hippocampus, a key component of the episodic and spatial memory system in both humans and rodents. Earlier studies have provided snapshots of morphological, molecular, physiological and behavioral changes in the hippocampus following either acute or repeated stress. However, the cumulative impact of repeated stress on in vivo hippocampal physiology remains unexplored. Here we report the stress-induced modulation of the spatially receptive fields of the hippocampal CA1 'place cells' as mice explore familiar and novel tracks after 5 and 10 days of immobilization stress. We find that similar to what has been observed following acute stress, five days of repeated stress results in decreased excitability of CA1 pyramidal cells. Following ten days of chronic stress, however, this decreased hippocampal excitability is no longer evident, suggesting adaptation may have occurred. In addition to these changes in neuronal excitability, we find deficient context discrimination, wherein both short-term and chronic stress impair the ability of the hippocampus to unambiguously distinguish novel and familiar environments. These results suggest that a loss of network flexibility may underlie some of the behavioral deficits accompanying chronic stress. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The ability to associate the consumption of a taste with its positive or negative consequences is fundamental to survival and influences the behavior of species ranging from invertebrate to human. As a result, for both research and clinical reasons, there has been a great effort to understand the neuronal circuits, as well as the cellular and molecular mechanisms, underlying taste learning. From a neuroanatomical perspective, the contributions of the cortex and amygdala are well documented; however, the literature is riddled with conflicting results regarding the role of the hippocampus in different facets of taste learning. Here, we use conditional genetics in mice to block NMDA receptor-dependent plasticity individually in each of the three major hippocampal subfields, CAI, CA3, and the dentate gyrus, via deletion of the NR1 subunit. Across the CAI, CA3, and dentate gyrus NR1 knock-out lines, we uncover a pattern of differential deficits that establish the dispensability of hippocampal plasticity in incidental taste learning, the requirement of CAI plasticity for associative taste learning, and a specific requirement for plasticity in the dentate gyrus when there is a long temporal gap between the taste and its outcome. Together, these data establish that the hippocampus is involved in associative taste learning and suggest an episodic component to this type of memory. [ABSTRACT FROM AUTHOR]

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 animal's 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. [ABSTRACT FROM AUTHOR]

Summary: Synaptic NMDA receptors (NMDARs) carry inward Ca2+ 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 Ca2+ 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. [Copyright &y& Elsevier]

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 hippocam-pus. 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. [ABSTRACT FROM AUTHOR]

The place cells and well-defined oscillatory population rhythms of the rodent hippocampus have served as a powerful model system in linking cells and circuits to memory function. While the initial three decades of place cell research primarily focused on the activity of neurons during exploration, the last twenty-five years have seen growing interest in the physiology of the hippocampus at rest. During slow-wave sleep and quiet wakefulness the hippocampus exhibits sharp-wave ripples (SWRs), short high-frequency, high-amplitude oscillations, that organize the reactivation or 'replay' of sequences of place cells, and interventions that disrupt SWRs impair learning. While the canonical model of SWRs generation have emphasized CA3 input to CA1 as the source of excitatory drive, recent work suggests there are multiple circuits, including the CA2 region, that can both influence, generate and organize SWRs, both from the oscillatory and information content perspectives in a task and state-dependent manner. This extended circuitry and its function must be considered for a true understanding of the role of the hippocampus in off-line processes such as planning and consolidation. • Sharp wave ripples and replay play a pivotal role in memory consolidation. • Chronic CA3 inhibition impairs replay quality and cross-hemisphere sychrony • CA2 organizes SWR activity, both from the oscillatory and information perspective. • SWRs have multiple origins and are shaped by intra & extra-hippocampal circuits. [ABSTRACT FROM AUTHOR]