Induction and modulation of persistent activity in a layer V PFC microcircuit model

Abstract

Working memory refers to the temporary storage of information and is strongly associated with the prefrontal cortex (PFC). Persistent activity of cortical neurons, namely the activity that persists beyond the stimulus presentation, is considered the cellular correlate of working memory. Although past studies suggested that this type of activity is characteristic of large scale networks, recent experimental evidence imply that small, tightly interconnected clusters of neurons in the cortex may support similar functionalities. However, very little is known about the biophysical mechanisms giving rise to persistent activity in small-sized microcircuits in the PFC. Here, we present a detailed biophysically—yet morphologically simplified—microcircuit model of layer V PFC neurons that incorporates connectivity constraints and is validated against a multitude of experimental data. We show that (a) a small-sized network can exhibit persistent activity under realistic stimulus conditions. (b) Its emergence depends strongly on the interplay of dADP, NMDA, and GABAB currents. (c) Although increases in stimulus duration increase the probability of persistent activity induction, variability in the stimulus firing frequency does not consistently influence it. (d) Modulation of ionic conductances (Ih, ID, IsAHP, IcaL, IcaN, IcaR) differentially controls persistent activity properties in a location dependent manner. These findings suggest that modulation of the microcircuit's firing characteristics is achieved primarily through changes in its intrinsic mechanism makeup, supporting the hypothesis of multiple bi-stable units in the PFC. Overall, the model generates a number of experimentally testable predictions that may lead to a better understanding of the biophysical mechanisms of persistent activity induction and modulation in the PFC.

Calcium regulation of HCN channels supports persistent activity in a multiscale model of neocortex

“…In the current study, we see how a persistent activity attractor landscape can be formed by complementing the effects of mutual excitation with the multiple complementary effects of excitatory and inhibitory interactions across cortical layers (Papoutsi et al, 2013, Papoutsi et al, 2014, Nelson et al, 2003, Marder et al, 1996). By contrast, Wang’s “bump attractor” network model was based on localized connectivity in a single layer of integrate-and-fire neurons (Compte et al, 2000, Wang, 2001).…”

Dendritic Nonlinearities Reduce Network Size Requirements and Mediate ON and OFF States of Persistent Activity in a PFC Microcircuit Model

“…Simulations were performed in a microcircuit model [9] composed of 7 pyramidal neurons and 2 inhibitory interneurons, all reciprocally connected (Figure 1A). Stimulus-induced persistent activity emerged (Figure 1B) when the NMDA current was enhanced by ∼75–100% (iNMDA-to-iAMPA = 1.9 or 2.3, control value = 1.1), simulating the increase of the NMDA current in L5 PFC pyramidal neurons due to dopamine release [24], [25], the recruitment of extrasynaptic receptors [19] or due to glia related-processes [20].…”

“…The microcircuit model includes seven pyramidal cells and two inhibitory interneurons reciprocally connected. Black arrows: excitatory connections, grey arrows: inhibitory connections (adapted with permission from [9]). Persistent activity is induced following external stimulation of the proximal apical dendrites (thick black arrow).…”

“…In the PFC, such microcircuits have been suggested to participate in persistent activity, the cellular correlate of working memory, but this hypothesis has not been rigorously tested [7], [8]. Towards this goal, Papoutsi and colleagues developed a layer 5 (L5) PFC microcircuit model, heavily constrained against experimental data, and showed that such microcircuits can serve as tunable modules of persistent activity [9]. What remain unclear are the biophysical and anatomical mechanisms that allow the induction (ON) and can cause termination (OFF) of persistent firing in such modules.…”

“…Here, we use our recently developed microcircuit model [9] to investigate the mechanisms that underlie persistent activity emergence (ON) and termination (OFF) at the dendritic, neuronal and network levels and search for the minimum network size required for expressing these states within physiological regimes. Moreover, we search for mechanisms that may underlie persistent activity maintenance upon presentation of distracting stimuli and identify network characteristics that code for the upcoming state transitions.…”