Long-lasting intrinsic persistent firing in rat CA1 pyramidal cells: A possible mechanism for active maintenance of memory

Abstract

The hippocampus is critical for memory tasks which require an active maintenance of memory for a short period of time; however, the underlying neural mechanisms remain unknown. Most theoretical and computational models, which date back to the classic proposals by Donald Hebb in , have been self-constrained by anatomy, as most models rely on the recurrent connectivity in region CA3 to support "reverberating activity" capable of memory maintenance. However, several physiological and behavioral studies have specifically implicated region CA1 in tasks which require an active maintenance of memory. Here, we demonstrate that despite limited recurrent connectivity, CA1 contains a robust cellular mechanism for active memory maintenance in the form of self-sustained persistent firing. Using in vitro whole-cell recordings, we demonstrate that brief stimulation (0.2-2 s) reliably elicits long-lasting (> 30 s) persistent firing that is supported by the calcium-activated non-selective cationic current. In contrast to more traditional ideas, these data suggest that the hippocampal region CA1 is capable of active maintenance of memory.

Mechanisms of Persistent Activity in Cortical Circuits: Possible Neural Substrates for Working Memory

“…prefrontal and temporal neocortex, the hippocampus and entorhinal cortex) is likely to include both synaptic circuit and intrinsic biophysical components. The potential involvement of intrinsic conductances in generating persistent firing comes, in part, from the common observation that simple intracellular depolarization can initiate firing that outlasts the stimulus even when synaptic transmission is blocked pharmacologically (Fransén et al 2006, Jochems & Yoshida 2013, Knauer et al 2013, Navaroli et al 2012, Pressler & Strowbridge 2006). Most of these studies involved adding exogenous modulators (typically drugs that activate muscarinic receptors, such as carbachol) that function to enhance excitability, perhaps mimicking the normal enhanced release of acetylcholine and other neuromodulators during heightened attention conditions associated with WM (see below).…”

“…First, the classic study (Egorov et al 2002) that demonstrated graded persistent firing used sharp microelectrodes instead of the now-ubiquitous whole-cell patch clamp recording method. Subsequent studies using patch clamp recordings did not observe graded persistent firing when the amplitude of the depolarizing step amplitude (Rahman & Berger 2011 in neocortex and Pressler & Strowbridge 2006 in the olfactory bulb) or step duration (Knauer et al 2013 and Jochems & Yoshida 2013 in the hippocampus) was varied [although Navaroli et al (2012) is an exception], perhaps reflecting the role of a key intracellular signaling molecule that is lost through diffusion in whole-cell recordings. Sharp microelectrode recordings also introduce potential complications, primarily related to lower input resistance due to current leakage around the microelectrode, leaving open the question of which intrinsic firing mode (bistable or graded/multistable) is most likely to occur endogenously.…”

Entorhinal–hippocampal neuronal circuits bridge temporally discontiguous events

“…Persistent firing has been defined as repetitive spiking activity of neurons that persists even after the triggering stimulus has been removed (Frank and Brown 2003;Major and Tank 2004) and is observed in a variety of brain regions including the MEC, hippocampal CA1 in vitro (Egorov et al 2002;Knauer et al 2013). The persistent firing of neurons in the MECIII (Yoshida et al 2008) may be one mechanism that contributes to temporal associative learning (Fig.…”

If I had a million neurons

“…Mechanisms for this process also exist on a cellular level (Tiganj et al, 2014). Individual neurons recorded in slice preparations often respond to a current injection with persistent spiking that continues for a period after the current injection, but may terminate at different intervals in different neurons, as shown in the postsubiculum (Yoshida and Hasselmo, 2009), the medial entorhinal cortex (Yoshida et al, 2008), and the hippocampus (Knauer et al, 2013). Recording from large populations would allow explicit testing of the full coding capability of a population, to determine if there is a decay of self-similarity across a population and within individual neurons that has the temporal resolution necessary to generate time cell responses, and to mediate the accuracy of behavioral timing estimates.…”