To support cognitive function, the CA3 region of the hippocampus performs computations involving attractor dynamics. Understanding how cellular and ensemble activities of CA3 neurons enable computation is critical for elucidating the neural correlates of cognition. Here we show that CA3 comprises not only classically described pyramid cells with thorny excrescences, but also includes previously unidentified 'athorny' pyramid cells that lack mossy-fiber input. Moreover, the two neuron types have distinct morphological and physiological phenotypes and are differentially modulated by acetylcholine. To understand the contribution of these athorny pyramid neurons to circuit function, we measured cell-type-specific firing patterns during sharp-wave synchronization events in vivo and recapitulated these dynamics with an attractor network model comprising two principal cell types. Our data and simulations reveal a key role for athorny cell bursting in the initiation of sharp waves: transient network attractor states that signify the execution of pattern completion computations vital to cognitive function.

Animals can store information about experiences by activating specific neuronal populations, and subsequent reactivation of these neural ensembles can lead to recall of salient experiences. In the hippocampus, granule cells of the dentate gyrus participate in such memory engrams; however, whether there is an underlying logic to granule cell participation has not been examined. Here, we find that a range of novel experiences preferentially activates granule cells of the suprapyramidal blade relative to the infrapyramidal blade. Motivated by this, we identify a suprapyramidal-blade-enriched population of granule cells with distinct spatial, morphological, physiological, and developmental properties. Via transcriptomics, we map these traits onto a sparse and discrete granule cell subtype that is recruited at a 10-fold greater frequency than expected by subtype prevalence, constituting the majority of all recruited granule cells. Thus, in behaviors known to involve hippocampal-dependent memory formation, a rare and spatially localized subtype dominates overall granule cell recruitment.

Kainic acid-induced status epilepticus (KA-SE) in mature rats results in the development of spontaneous recurrent seizures and a pattern of cell death resembling hippocampal sclerosis in patients with temporal lobe epilepsy. In contrast, KA-SE in young animals before postnatal day (P) 18 is less likely to cause cell death or epilepsy. To investigate whether changes in neuronal excitability occur in the subiculum after KA-SE, we examined the age-dependent effects of SE on the bursting neurons of subiculum, the major output region of the hippocampus. Patch-clamp recordings were used to monitor bursting in pyramidal neurons in the subiculum of rat hippocampal slices. Neurons were studied either one or 2-3 weeks following injection of KA or saline (control) in immature (P15) or more mature (P30) rats, which differ in their sensitivity to KA as well as the long-term sequelae of the KA-SE. A significantly greater proportion of subicular pyramidal neurons from P15 rats were strong-bursting neurons and showed increased frequency-dependent bursting compared to P30 animals. Frequency-dependent burst firing was enhanced in P30, but not in P15 rats following KA-SE. The enhancement of bursting induced by KA-SE in more mature rats suggests that the frequency-dependent limitation of repetitive burst firing, which normally occurs in the subiculum, is compromised following SE. These changes could facilitate the initiation of spontaneous recurrent seizures or their spread from the hippocampus to other parts of the brain.

Proper brain function requires the precise localization of proteins and signaling molecules on a nanometer scale. The examination of molecular organization at this scale has been difficult in part because it is beyond the reach of conventional, diffraction-limited light microscopy. The recently developed method of superresolution, localization-based fluorescent microscopy (LBM), such as photoactivated localization microscopy (PALM) and stochastic optical reconstruction microscopy (STORM), has demonstrated a resolving power at a 10 nm scale and is poised to become a vital tool in modern neuroscience research. Indeed, LBM has revealed previously unknown cellular architectures and organizational principles in neurons. Here, we discuss the principles of LBM, its current applications in neuroscience, and the challenges that must be met before its full potential is achieved. We also present the unpublished results of our own experiments to establish a sample preparation procedure for applying LBM to study brain tissue. Synapse, 69:283-294, 2015. © 2015 Wiley Periodicals, Inc.

The way the hippocampus processes information and encodes memories in the form of "cell assemblies" is likely determined in part by how its circuits are wired up during development. In this issue, Xu et al. now provide new insight into how neurons arising from a single common precursor migrate to their final destination and form functionally synchronous ensembles.

Many brain functions depend on the ability of neural networks to temporally integrate transient inputs to produce sustained discharges. This can occur through cell-autonomous mechanisms in individual neurons and through reverberating activity in recurrently connected neural networks. We report a third mechanism involving temporal integration of neural activity by a network of astrocytes. Previously, we showed that some types of interneurons can generate long-lasting trains of action potentials (barrage firing) following repeated depolarizing stimuli. Here we show that calcium signaling in an astrocytic network correlates with barrage firing; that active depolarization of astrocyte networks by chemical or optogenetic stimulation enhances; and that chelating internal calcium, inhibiting release from internal stores, or inhibiting GABA transporters or metabotropic glutamate receptors inhibits barrage firing. Thus, networks of astrocytes influence the spatiotemporal dynamics of neural networks by directly integrating neural activity and driving barrages of action potentials in some populations of inhibitory interneurons.

Neuronal computation involves the integration of synaptic inputs that are often distributed over expansive dendritic trees, suggesting the need for compensatory mechanisms that enable spatially disparate synapses to influence neuronal output. In hippocampal CA1 pyramidal neurons, such mechanisms have indeed been reported, which normalize either the ability of distributed synapses to drive action potential initiation in the axon or their ability to drive dendritic spiking locally. Here we report that these mechanisms can coexist, through an elegant combination of distance-dependent regulation of synapse number and synaptic expression of AMPA and NMDA receptors. Together, these complementary gradients allow individual dendrites in both the apical and basal dendritic trees of hippocampal neurons to operate as facile computational subunits capable of supporting both global integration in the soma/axon and local integration in the dendrite.

Understanding the structure of single neurons is critical for understanding how they function within neural circuits. BigNeuron is a new community effort that combines modern bioimaging informatics, recent leaps in labeling and microscopy, and the widely recognized need for openness and standardization to provide a community resource for automated reconstruction of dendritic and axonal morphology of single neurons.

Understanding the structure of single neurons is critical for understanding how they function within neural circuits. BigNeuron is a new community effort that combines modern bioimaging informatics, recent leaps in labeling and microscopy, and the widely recognized need for openness and standardization to provide a community resource for automated reconstruction of dendritic and axonal morphology of single neurons.

Brain-derived neurotrophic factor (BDNF) plays an important role in hippocampus-dependent learning and memory. Canonically, this has been ascribed to an enhancing effect on neuronal excitability and synaptic plasticity in the CA1 region. However, it is the pyramidal neurons in the subiculum that form the primary efferent pathways conveying hippocampal information to other areas of the brain, and yet the effect of BDNF on these neurons has remained unexplored. We present new data that BDNF regulates neuronal excitability and cellular plasticity in a much more complex manner than previously suggested. Subicular pyramidal neurons can be divided into two major classes, which have different electrophysiological and morphological properties, different requirements for the induction of plasticity and different extra-hippocampal projections. We found that BDNF increases excitability in one class of subicular pyramidal neurons, yet decreases excitability of the other class. Further, while endogenous BDNF was necessary for the induction of synaptic plasticity in both cell types, BDNF enhanced intrinsic plasticity in one class of pyramidal neurons, yet suppressed intrinsic plasticity in the other. Taken together, these data suggest a novel role for BDNF signaling, as it appears to dynamically and bidirectionally regulate the output of hippocampal information to different regions of the brain.

Cells regulate function by synthesizing and degrading proteins. This turnover ranges from minutes to weeks, as it varies across proteins, cellular compartments, cell types, and tissues. Current methods for tracking protein turnover lack the spatial and temporal resolution needed to investigate these processes, especially in the intact brain, which presents unique challenges. We describe a pulse-chase method (DELTA) for measuring protein turnover with high spatial and temporal resolution throughout the body, including the brain. DELTA relies on rapid covalent capture by HaloTag of fluorophores that were optimized for bioavailability in vivo. The nuclear protein MeCP2 showed brain region- and cell type-specific turnover. The synaptic protein PSD95 was destabilized in specific brain regions by behavioral enrichment. A novel variant of expansion microscopy further facilitated turnover measurements at individual synapses. DELTA enables studies of adaptive and maladaptive plasticity in brain-wide neural circuits.