Multiple Approaches to the Investigation of Cell Assembly in Memory Research—Present and Future

Abstract

In this review article we focus on research methodologies for detecting the actual activity of cell assemblies, which are populations of functionally connected neurons that encode information in the brain. We introduce and discuss traditional and novel experimental methods and those currently in development and briefly discuss their advantages and disadvantages for the detection of cell-assembly activity. First, we introduce the electrophysiological method, i.e., multineuronal recording, and review former and recent examples of studies showing models of dynamic coding by cell assemblies in behaving rodents and monkeys. We also discuss how the firing correlation of two neurons reflects the firing synchrony among the numerous surrounding neurons that constitute cell assemblies. Second, we review the recent outstanding studies that used the novel method of optogenetics to show causal relationships between cell-assembly activity and behavioral change. Third, we review the most recently developed method of live-cell imaging, which facilitates the simultaneous observation of firings of a large number of neurons in behaving rodents. Currently, all these available methods have both advantages and disadvantages, and no single measurement method can directly and precisely detect the actual activity of cell assemblies. The best strategy is to combine the available methods and utilize each of their advantages with the technique of operant conditioning of multiple-task behaviors in animals and, if necessary, with brain–machine interface technology to verify the accuracy of neural information detected as cell-assembly activity.

Dynamic patterns of correlated activity in the prefrontal cortex encode information about social behavior

“…During complex behaviors, the brain can use many strategies to represent information about the external environment and internal state of the organism. The term ‘ensemble’ is often used to refer to a group of neurons whose activity is similarly modulated (either increased or decreased) during specific behaviors (Sakurai, 1999; Cai et al , 2016; Sakurai et al , 2018; Corder et al , 2019; Ghandour et al , 2019; Gründemann et al , 2019). It is generally accepted that ensembles transmit behavioral information via changes in the activity levels of their constituent neurons.…”

Temporal Flexibility of Systems Consolidation and the Synaptic Occupancy/Reset Theory (SORT): Cues About the Nature of the Engram

“…Besides, theories are no better than the experimental data available in their support. Here, the challenge is being able to directly probe the engram , a concept originally introduced by Richard Semon (Semon, 1904; Josselyn et al, 2017), and considered intractable until the recent emergence of new, powerful recording and labeling technological tools, such as optogenetics (Cowansage et al, 2014; Nabavi et al, 2014; Tonegawa et al, 2015a,b; Cai et al, 2016; Rashid et al, 2016) and chemogenetics (Roth, 2016; Atasoy and Sternson, 2018; Campbell and Marchant, 2018; Muir et al, 2018), usually combined with multineuronal recordings (Sakurai et al, 2018). Optogenetics, outstanding and promising as it is (Goshen, 2014; Bickle, 2016), still has to evolve as a methodology considering the technical limitations that reduce their interpretability (see Baxter and Croxson, 2013; Hardt and Nadel, 2018).…”

“…SORT proposes that CA1 cells establish strong synapses with previously available, yet not connected efferent axons projecting to the cortex, thus recruiting the exact set of cortical components that compose the engram. It is reasonable to consider that a direct test of this hypothesis is not technically feasible right now, at least not employing present optogenetic tools that lack resolution both in the spatial (diffusion covers only small volumes) and the temporal (fast on/off control might not reflect the longer temporal framework necessary for plastic changes to take place) domains, among other limitations (Baxter and Croxson, 2013; Kim et al, 2016; Hardt and Nadel, 2018; Sakurai et al, 2018). Thus, to visualize the whole set of CA1 (pyramidal cells’) plastic synapses that might specifically be involved in connecting to those axonal efferences projecting to NCTX, it may be much more adequate to employ fluorescent microscopy.…”

“…Thus, to visualize the whole set of CA1 (pyramidal cells’) plastic synapses that might specifically be involved in connecting to those axonal efferences projecting to NCTX, it may be much more adequate to employ fluorescent microscopy. These techniques allow for the imaging of dendritic spine dynamics itself, and include confocal laser scanning, transcranial two/multi-photon microscopes, or fiber-optics endomicroscopy (Maiti et al, 2015; Sakurai et al, 2018). They have already been proven efficient to image hippocampal place cells activity in subcellular resolution during navigation (Dombeck et al, 2010), and even to study long-term memory related neural ensemble activity in the amygdala (Grewe et al, 2017).…”

Donald O. Hebb and the Organization of Behavior: 17 years in the writing

“…The Organization of Behavior introduced the concepts of the "Hebb synapse", the "Hebbian cell assembly" and the "Phase Sequence". While the Hebb synapse has become the most cited, and "better known than Donald Hebb himself" [166], the cell assembly may be his most lasting legacy [41,97,122,153,163]. Research on the phase sequence has lagged behind, but multi-electrode recording techniques have enabled researchers to investigate the integration of cell assemblies into larger phase sequences [4,129].…”