Basal tree complexity shapes functional pathways in the prefrontal cortex.

While the morphology of basal dendritic trees in cortical pyramidal neurons varies, the functional implications of this diversity are just starting to emerge. In layer 5 pyramidal neurons of the prefrontal cortex, for example, increased basal tree complexity determines the recruitment of these neurons into functional circuits. Here, we use a modeling approach to investigate whether and how the morphology of the basal tree mediates the functional output of neurons. We implemented 57 basal tree morphologies of layer 5 prefrontal pyramidal neurons of the rat and identified morphological types that were characterized by different response features, forming distinct functional types. These types were robust to a wide range of manipulations (distribution of active ionic mechanisms, NMDA conductance, somatic and apical tree morphology, or the number of activated synapses) and supported different temporal coding schemes at both the single neuron and the microcircuit level. We predict that the basal tree morphological diversity among neurons of the same class mediates their segregation into distinct functional pathways. Extension of our approach/findings to other cortical areas and/or layers or under pathological conditions may provide a generalized role of the basal trees for neuronal function.NEW & NOTEWORTHY Our results suggest that the segregation of neurons to different functional types based on their basal tree morphology is in large part independent of the distribution of active ionic mechanisms, NMDA conductance, somatic and apical tree morphology, and the number of activated synapses; different functional types support distinct temporal coding schemes. This can be exploited to create networks with diverse coding characteristics, thus contributing to the functional heterogeneity within the same layer and area.

The dendritic engram.

Accumulating evidence from a wide range of studies, including behavioral, cellular, molecular and computational findings, support a key role of dendrites in the encoding and recall of new memories. Dendrites can integrate synaptic inputs in non-linear ways, provide the substrate for local protein synthesis and facilitate the orchestration of signaling pathways that regulate local synaptic plasticity. These capabilities allow them to act as a second layer of computation within the neuron and serve as the fundamental unit of plasticity. As such, dendrites are integral parts of the memory engram, namely the physical representation of memories in the brain and are increasingly studied during learning tasks. Here, we review experimental and computational studies that support a novel, dendritic view of the memory engram that is centered on non-linear dendritic branches as elementary memory units. We highlight the potential implications of dendritic engrams for the learning and memory field and discuss future research directions.

GABAergic Interneurons with Nonlinear Dendrites: From Neuronal Computations to Memory Engrams.

GABAergic interneurons (INs) are a highly diverse class of neurons in the mammalian brain with a critical role in orchestrating multiple cognitive functions and maintaining the balance of excitation/inhibition across neuronal circuitries. In this perspective, we discuss recent findings regarding the ability of some IN subtypes to integrate incoming inputs in nonlinear ways within their dendritic branches. These recently discovered features may endow the specific INs with advanced computing capabilities, whose breadth and functional contributions remain an open question. Along these lines, we discuss theoretical and experimental evidence regarding the potential role of nonlinear IN dendrites in advancing single neuron computations and contributing to memory formation.

A locus coeruleus-dorsal CA1 dopaminergic circuit modulates memory linking.

Individual memories are often linked so that the recall of one triggers the recall of another. For example, contextual memories acquired close in time can be linked, and this is known to depend on a temporary increase in excitability that drives the overlap between dorsal CA1 (dCA1) hippocampal ensembles that encode the linked memories. Here, we show that locus coeruleus (LC) cells projecting to dCA1 have a key permissive role in contextual memory linking, without affecting contextual memory formation, and that this effect is mediated by dopamine. Additionally, we found that LC-to-dCA1-projecting neurons modulate the excitability of dCA1 neurons and the extent of overlap between dCA1 memory ensembles as well as the stability of coactivity patterns within these ensembles. This discovery of a neuromodulatory system that specifically affects memory linking without affecting memory formation reveals a fundamental separation between the brain mechanisms modulating these two distinct processes.

Synaptic Clustering and Memory Formation.

In the study of memory engrams, synaptic memory allocation is a newly emerged theme that focuses on how specific synapses are engaged in the storage of a given memory. Cumulating evidence from imaging and molecular experiments indicates that the recruitment of synapses that participate in the encoding and expression of memory is neither random nor uniform. A hallmark observation is the emergence of groups of synapses that share similar response properties and/or similar input properties and are located within a stretch of a dendritic branch. This grouping of synapses has been termed "synapse clustering" and has been shown to emerge in many different memory-related paradigms, as well as in in vitro studies. The clustering of synapses may emerge from synapses receiving similar input, or via many processes which allow for cross-talk between nearby synapses within a dendritic branch, leading to cooperative plasticity. Clustered synapses can act in concert to maximally exploit the nonlinear integration potential of the dendritic branches in which they reside. Their main contribution is to facilitate the induction of dendritic spikes and dendritic plateau potentials, which provide advanced computational and memory-related capabilities to dendrites and single neurons. This review focuses on recent evidence which investigates the role of synapse clustering in dendritic integration, sensory perception, learning, and memory as well as brain dysfunction. We also discuss recent theoretical work which explores the computational advantages provided by synapse clustering, leading to novel and revised theories of memory. As an eminent phenomenon during memory allocation, synapse clustering both shapes memory engrams and is also shaped by the parallel plasticity mechanisms upon which it relies.

Challenging the point neuron dogma: FS basket cells as 2-stage nonlinear integrators.

Interneurons are critical for the proper functioning of neural circuits. While often morphologically complex, their dendrites have been ignored for decades, treating them as linear point neurons. Exciting new findings reveal complex, non-linear dendritic computations that call for a new theory of interneuron arithmetic. Using detailed biophysical models, we predict that dendrites of FS basket cells in both hippocampus and prefrontal cortex come in two flavors: supralinear, supporting local sodium spikes within large-volume branches and sublinear, in small-volume branches. Synaptic activation of varying sets of these dendrites leads to somatic firing variability that cannot be fully explained by the point neuron reduction. Instead, a 2-stage artificial neural network (ANN), with sub- and supralinear hidden nodes, captures most of the variance. Reduced neuronal circuit modeling suggest that this bi-modal, 2-stage integration in FS basket cells confers substantial resource savings in memory encoding as well as the linking of memories across time.

Hotspots of dendritic spine turnover facilitate clustered spine addition and learning and memory.

Modeling studies suggest that clustered structural plasticity of dendritic spines is an efficient mechanism of information storage in cortical circuits. However, why new clustered spines occur in specific locations and how their formation relates to learning and memory (L&M) remain unclear. Using in vivo two-photon microscopy, we track spine dynamics in retrosplenial cortex before, during, and after two forms of episodic-like learning and find that spine turnover before learning predicts future L&M performance, as well as the localization and rates of spine clustering. Consistent with the idea that these measures are causally related, a genetic manipulation that enhances spine turnover also enhances both L&M and spine clustering. Biophysically inspired modeling suggests turnover increases clustering, network sparsity, and memory capacity. These results support a hotspot model where spine turnover is the driver for localization of clustered spine formation, which serves to modulate network function, thus influencing storage capacity and L&M.

with Love, from Post to Pre.

In this issue of Neuron, Costa et al. (2017) introduce a theoretical framework that predicts the ratio of presynaptic and postsynaptic changes taking place during LTP and LTD and show that these processes co-operate so as to optimize the postsynaptic response statistics.

Linking Memories across Time via Neuronal and Dendritic Overlaps in Model Neurons with Active Dendrites.

Memories are believed to be stored in distributed neuronal assemblies through activity-induced changes in synaptic and intrinsic properties. However, the specific mechanisms by which different memories become associated or linked remain a mystery. Here, we develop a simplified, biophysically inspired network model that incorporates multiple plasticity processes and explains linking of information at three different levels: (1) learning of a single associative memory, (2) rescuing of a weak memory when paired with a strong one, and (3) linking of multiple memories across time. By dissecting synaptic from intrinsic plasticity and neuron-wide from dendritically restricted protein capture, the model reveals a simple, unifying principle: linked memories share synaptic clusters within the dendrites of overlapping populations of neurons. The model generates numerous experimentally testable predictions regarding the cellular and sub-cellular properties of memory engrams as well as their spatiotemporal interactions.

Synaptic clustering within dendrites: an emerging theory of memory formation.

It is generally accepted that complex memories are stored in distributed representations throughout the brain, however the mechanisms underlying these representations are not understood. Here, we review recent findings regarding the subcellular mechanisms implicated in memory formation, which provide evidence for a dendrite-centered theory of memory. Plasticity-related phenomena which affect synaptic properties, such as synaptic tagging and capture, synaptic clustering, branch strength potentiation and spinogenesis provide the foundation for a model of memory storage that relies heavily on processes operating at the dendrite level. The emerging picture suggests that clusters of functionally related synapses may serve as key computational and memory storage units in the brain. We discuss both experimental evidence and theoretical models that support this hypothesis and explore its advantages for neuronal function.

Coding and decoding with dendrites.

Since the discovery of complex, voltage dependent mechanisms in the dendrites of multiple neuron types, great effort has been devoted in search of a direct link between dendritic properties and specific neuronal functions. Over the last few years, new experimental techniques have allowed the visualization and probing of dendritic anatomy, plasticity and integrative schemes with unprecedented detail. This vast amount of information has caused a paradigm shift in the study of memory, one of the most important pursuits in Neuroscience, and calls for the development of novel theories and models that will unify the available data according to some basic principles. Traditional models of memory considered neural cells as the fundamental processing units in the brain. Recent studies however are proposing new theories in which memory is not only formed by modifying the synaptic connections between neurons, but also by modifications of intrinsic and anatomical dendritic properties as well as fine tuning of the wiring diagram. In this review paper we present previous studies along with recent findings from our group that support a key role of dendrites in information processing, including the encoding and decoding of new memories, both at the single cell and the network level.