Memory  >   Memory Consolidation: Astrocytes Regulate the UP State

The UP state refers to the depolarizing phase of slow oscillations, which occur only in slow wave sleep, not in wake or other sleep stages (Chapter 33). A few studies have revealed that slow oscillations originate in the medial prefrontal cortex (mPFC) (Nir et al., 2011; Massimini et al., 2004). The anterior cingulate cortex (ACC) is located within mPFC. During slow wave sleep, the majority of ACC neurons are activated just before hippocampal sharp wave ripples (SWRs) (Wang and Ikemoto, 2016). This result corroborates the finding that the cortical UP state preceded SWRs (Mölle et al., 2006; Isomura et al., 2006). Hence, the engram cells in mPFC should be able to reactivate spontaneously, without stimulation by SWRs. Its underlying mechanism is discussed in this chapter.

Memories are Encoded in mPFC at the Time of Learning

The enduring memory was thought to be formed in sequence: initially encoded in the hippocampus, and then gradually transferred to the neocortex (McClelland et al., 1995). This idea "has lost support" (Tononi and Cirelli, 2014). Over the last two decades, accumulating evidence suggests that memories are also stored in mPFC from the time of learning (Blum et al., 2006; Genzel et al., 2017; Albo and Gräff, 2018). This finding is essential to explain why the slow oscillations originate in mPFC.

Spontaneous Generation of NMDA Plateaus in mPFC

The NMDA plateau (also called "dendritic plateau potential") resembles the UP state of the slow oscillation (Oikonomou et al., 2014), suggesting that the UP state could originate from NMDA plateaus, which in turn arise from synchronized opening of NMDARs located in the basal dendrites of engram cells. This notion is supported by the finding that blocking NMDARs abolishes the UP state (Castro-Alamancos and Favero, 2015).

Strong stimulation may cause GluN2B-containing NMDARs to enter an extinction state as reflected in short term potentiation. In this case, the generation of NMDA plateaus requires two conditions: (1) recovery from NMDAR extinction (i.e., dissociation of CABT from NMDARs), and (2) a substantial glutamate pond. Norepinephrine (NE) and acetylcholine (ACh) may play a crucial role in the recovery from NMDAR extinction, as detailed in Chapter 24 and Chapter 25. However, during slow wave sleep, the recovery from NMDAR extinction is induced by NE based on both experimental evidence (Chapter 33) and theoretical consideration (Chapter 36).

In the awake state, SWRs may provide the required glutamate (Chapter 32), resulting in hippocampal replay, which is essentially a memory retrieval process in the absence of reminding cues. In the slow wave sleep, the slow oscillation occurred before SWRs. Where does the glutamate come from?

The Role of Astrocytes


Figure 34-1. The glutamate released from glial cells is the major source of glutamate pond. [Source: Oikonomou et al., 2012]

The glutamate pond originates from two sources: (1) synaptic spillover and (2) release from astrocytes (the major type of glial cells) (Oikonomou et al., 2012). The basal dendrites are surrounded by dense glial cells capable of absorbing glutamate (Oikonomou et al., 2014). During slow wave sleep, astrocytes may reverse their function from glutamate uptake to glutamate release. Astrocytes have been shown to regulate the UP state (Poskanzer and Yuste, 2011; Poskanzer and Yuste, 2016) and play a critical role in the synchronization of the memory engram network during the UP state (Szabó et al., 2017).

The glutamate can be released from astrocytes via several different mechanisms. One of them is Ca2+- dependent exocytosis (Malarkey and Parpura, 2008). Indeed, intracellular injection of a calcium chelator into individual astrocytes has been shown to inhibit spontaneous and stimulated UP states (Poskanzer and Yuste, 2011). Furthermore, the adenosine level is known to increase during sleep (Bjorness and Greene, 2009), which may activate its A1 receptor (A1R) to increase the activity of phospholipase C (PLC) (Biber et al., 1997; Jacobson and Gao, 2006), resulting in the release of Ca2+ from intracellular stores (endoplasmic reticulum) via IP3 (see this article). The surge of intracellular Ca2+ then triggers cortical UP states via the Ca2+- dependent exocytosis of glutamate. In support of this mechanism, A1R antagonist cyclopentyltheophylline (CPT) has been demonstrated to reduce UP states significantly (Poskanzer and Yuste, 2011).


Figure 34-2. The signaling cascade leading to the UP state during slow wave sleep. The glutamate pond typically activates mGluR5. During wakefulness, mGluR5 signaling may lead to the release of Ca2+ from intracellular stores and activate adenylyl cyclase type 1 or 8, thereby contributing to memory retrieval (Chapter 36). However, during slow wave sleep, mGluR5 is uncoupled from IP3 receptor (Chapter 37), preventing the release of Ca2+ from intracellular stores. This may ensure that the slow oscillation is controlled by norepinephrine.

Although SWRs do not directly initiate the UP state, they could play a key role in targeting the potentiated memory units that demand strengthening. During learning, only the astrocytes located in the memory units that have been potentiated may absorb extracellular glutamate in the glutamate pond. Subsequently, the SWRs generated in wake also send glutamatergic input from CA1 to the same ensemble of memory units. Therefore, at the time of slow wave sleep, only the astrocytes located in these potentiated memory units contain ample glutamate to initiate the UP state. The slow oscillation originates in mPFC because CA1 has strong direct projections to the mPFC (Jin and Maren, 2015).


Author: Frank Lee
First published: July, 2018