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Crosstalk between the Subiculum and Sleep-Wake Regulation: A Review

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25 September 2023

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27 September 2023

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Abstract
This review provides an overview of the current understanding of the neural systems involved in regulating wakefulness, non-rapid eye movement sleep (NREMS), and rapid eye movement sleep (REMS) in mammals. Specifically, we focus on the anatomical connections between the subiculum, a component of the hippocampal formation, and the regions responsible for regulating the sleep-wake cycle. The subiculum exhibits direct connections with key areas involved in sleep regulation, such as the lateral hypothalamus, tuberomammillary nucleus, basal forebrain, ventrolateral preoptic nucleus, ventrolateral tegmental area, and suprachiasmatic nucleus. Additionally, second-order projections from the subiculum are received by the laterodorsal tegmental nucleus and locus coeruleus, suggesting potential involvement of the subiculum in the regulation of circadian rhythms, particularly the circadian sleep-wake cycle. We also discuss alterations in the subiculum observed in individuals with sleep disorders and sleep-deprived mice, underscoring the significance of investigating neuronal communication between the subiculum and pathways promoting both sleep and wakefulness.
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Subject: Biology and Life Sciences  -   Neuroscience and Neurology

1. Introduction

Natural Sleep, a phenomenon observed in all animals, particularly mammals, continues to be a scientific enigma. Extensive research has consistently unveiled distinct manifestations of sleep in vertebrate and invertebrate animals (Eban-Rothschild et al., 2018). In mammals, vigilance states are typically characterized through the use of electroencephalogram (EEG) and electromyogram (EMG) recordings, which measure global cortical and muscular activities, respectively. This classification delineates vigilance states into three main phases: wakefulness, non-rapid eye movement sleep (NREMS), and rapid eye movement sleep (REMS) (Weber and Dan, 2016).
The wakeful state displays heterogeneity characterized by unsynchronized EEG oscillations of low amplitude and mixed frequencies, along with variable muscle activity. NREMS is defined by high-amplitude, low-frequency delta oscillations (0.5–4 Hz) and spindles (bursts of 7–15 Hz oscillations) in the EEG, accompanied by reduced postural muscle tone. During REMS, the EEG predominantly exhibits theta (5-10 Hz) and gamma oscillations (25-80 Hz), while the axial posture muscles experience a complete loss of muscle tone (Eban-Rothschild et al., 2018) (Figure 1).
The mouse EEG data were recorded at the Department of Anesthesiology & Intensive Care, School of Medicine, Technical University of Munich, under license: ROB-55.2-2532.Vet_02-19-121. The human EEG recordings for (C) and (D) are sourced from the Sleep-EDF Database v1.0.0 (Kemp et al., 2018).In contrast to humans, who typically experience 5 to 6 sleep cycles alternating between NREMS and REMS during monophasic sleep, rodents follow a polyphasic sleep pattern distributed across their circadian behavior (Sulaman et al., 2023). Understanding the neural mechanisms underpinning this behavior is of profound scientific interest and clinical significance, given that sleep plays a vital role in cognitive and physiological functions as well as overall health (Gupta et al., 2013; Kahn, 2023).
Early anatomists and neurologists, including Purkinje, expressed skepticism regarding the existence of specific neural mechanisms responsible for controlling wakefulness and sleep (Scammell et al., 2017). Nevertheless, pioneering work by von Economo in the early last century (ECONOMO, 1930) laid the foundation for our understanding of the neuronal mechanisms underlying sleep-wake regulation in mammals. Following the discovery of the ascending reticular activating system in 1949 (Moruzzi and Magoun, 1949), we have made significant strides in unraveling the neural circuits that support wakefulness. In contrast, elucidating the neural mechanisms responsible for generating sleep has proven to be more challenging. Recent studies utilizing techniques like cell- and region-specific pharmacological manipulations have led to transformative advancements in our understanding of sleep regulation. They have unveiled numerous brain systems that selectively modulate our arousal states. However, the specific neuronal populations responsible for initiating and maintaining NREMS or REMS, as well as their interconnections, remain largely speculative. The brain nuclei responsible for controlling sleep-wake states are typically heterogeneous, housing mixed neuronal populations that can maintain various vigilance states (Eban-Rothschild et al., 2018; Weber and Dan, 2016).
Enhancing our understanding of the brain mechanisms that regulate sleep-wake behavior holds promise for gaining new insights into the functions of sleep and advancing the development of more effective treatments for sleep disorders.
In this paper, we provide a concise overview of sleep-wake regulatory areas and explore the anatomy of the subiculum, along with its primary functions. By reviewing the anatomical connections between the subiculum and the regions involved in regulating sleep-wake behavior, we also address observed changes in the subiculum among individuals with sleep disorders. Additionally, we examine the state-dependent alterations in subicular function observed in sleep-deprived mice. These findings underscore the importance of investigating the interaction between the subiculum and sleep regulation.

2. Sleep-wake promoting areas

The regulation of the transition from wakefulness to sleep involves complex interactions between physiological conditions, sleep homeostasis, and intrinsic circadian fluctuations. Multiple brain regions play crucial roles in this process, with some areas serving dual functions in promoting sleep and maintaining wakefulness (Figure 2).
BF: Basal Forebrain; DRN: Dorsal Raphe Nucleus; LC: Locus Coeruleus; LDT: Laterodorsal Tegmentum; MRN: Median Raphe Nucleus; PB: Parabrachial Nucleus; PPT: Pedunculopontine Nucleus; PZ: Parafacial Zone; SCN: Suprachiasmatic Nucleus; SLD: Sub-Laterodorsal (Tegmental) Nucleus; TMN: Tuberomammillary Nucleus; vPAG: Ventral Periaqueductal Gray; VTA: Ventral Tegmental Area
One such region is the lateral hypothalamus (LH), housing both sleep-active and wake-active neurons. Sleep-active neurons expressing melanin-concentrating hormone (MCH) in the LH are most active during REMS (Hassani et al., 2009; Kroeger et al., 2019; Varin et al., 2018). These neurons promote the initiation of REMS by inhibiting wake-promoting neurons in various brain areas, including the tuberomammillary nucleus (TMN), the locus coeruleus (LC), and the dorsal raphe nucleus (DRN) (Jego et al., 2013). The chronic activity of MCH neurons influences not only REMS but also NREMS (Konadhode et al., 2013). Additionally, hypocretin/orexin neurons in the LH play a crucial role in regulating the sleep-wake cycle (Latifi et al., 2018). Loss of these neurons leads to narcolepsy in various species, including humans (Thannickal et al., 2000) and rodents (Chemelli et al., 1999). Glutamatergic and GABAergic neurons in the LH region are crucial in inducing and maintaining wakefulness, and their inhibition enhances sleep (Herrera et al., 2016; Venner et al., 2016).
Von Economo's research in 1930 unveiled a correlation between damage to the preoptic hypothalamus area (POA) and insomnia in human patients (ECONOMO, 1930). The ventral lateral preoptic (VLPO) and median preoptic nucleus (MnPO) regions contain a dense population of neurons responsible for regulating sleep (Horner and Peever, 2017). Selective lesions in the VLPO significantly reduce NREMS (Lu et al., 2000). During sleep, GABAergic neurons in the VLPO and MnPO regions inhibit arousal regulatory systems, including the LH, posterior hypothalamus, DRN, LC, ventral periaqueductal gray matter (vPAG), and parabrachial nucleus (PB), thereby promoting sleep (Weber and Dan, 2016).
Adjacent to the POA, the basal forebrain (BF), is a critical region for both sleep and wakefulness (Takahashi et al., 2009). The majority of BF neurons are GABAergic, with a small fraction expressing acetylcholine or glutamate (Sulaman et al., 2023). Cholinergic neurons are active during wakefulness and REMS, inhibiting slow-wave delta oscillations (Han et al., 2014). BF GABAergic neurons exhibit mixed functions, with parvalbumin-expressing (PV) GABAergic neurons involved in rapid transitions from NREMS to wakefulness (McKenna et al., 2020), while somatostatin-expressing (SOM) GABAergic neurons promote NREMS (Xu et al., 2015). Glutamatergic neurons in the BF influence REMS by modulating theta rhythm (Xu et al., 2015).
The LC serves as a vital arousal-center, with its noradrenergic neurons promoting wakefulness (Liang et al., 2021). Their activity decreases during NREMS and ceases during REMS (Aston-Jones and Bloom, 1981; Hobson et al., 1975). Within the ventral tegmental area (VTA), a region containing numerous dopaminergic, glutamatergic, and GABAergic neurons, the dopaminergic neurons predominantly regulate sleep and wakefulness (Morales and Margolis, 2017). Optogenetic and chemogenetic stimulation of VTA dopaminergic and glutamatergic neurons induces wakefulness (Eban-Rothschild et al., 2016; Oishi et al., 2017), while inhibiting these neurons results in robust NREMS activation (Eban-Rothschild et al., 2016; Yu et al., 2019). GABAergic VTA neurons restrict wakefulness by inhibiting arousal-promoting VTA glutamatergic and/or dopaminergic neurons, as well as through projections to the LH (Yu et al., 2019).
The dorsal and median raphe nuclei (DRN and MRN) contribute to sleep regulation through serotonergic neurons (Sulaman et al., 2023). The firing pattern of DRN serotonergic neurons increases during wakefulness and decreases during REMS (Trulson and Jacobs, 1979). These serotonergic neurons promote relaxed wakefulness while inhibiting REMS (Jacobs and Fornal, 1993). Rasmussen et al. reported a group of presumed 5-HT neurons in the MRN with similar activity patterns to "classic" 5-HT neurons in the DRN (Rasmussen et al., 1984). Recent research in mice has shown that GABAergic neurons in the LH selectively suppress GABAergic neurons in the DRN, leading to increased activity in a significant portion of LH neurons, thereby promoting arousal (Gazea et al., 2021). MRN suppresses or blocks theta rhythm during NREMS, while silencing the MRN during REMS allows its expression (Vertes, 2010).
The brainstem pedunculopontine (PPT) and laterodorsal tegmental (LDT) nuclei house cholinergic neurons, maximally active during wakefulness and REMS, and GABAergic neurons, active solely during REMS (Boucetta et al., 2014). In the parafacial zone (PZ), GABAergic/glycinergic neurons regulate NREM sleep, with their stimulation leading to prolonged NREM sleep (Anaclet et al., 2014; Anaclet et al., 2018). The glutamatergic sublaterodorsal nucleus (SLD) is involved in muscle atony during REMS (Boissard et al., 2002).

3. Subiculum, and its interaction with sleep

The hippocampus, dentate gyrus (DG), and subiculum together constitute the hippocampal formation, which plays a pivotal role in functions such as learning, memory, and orientation (van Strien et al., 2009). Among these components, the subiculum stands out as the principal output region of the hippocampal formation. It serves not only as a relay for information but also as a unique processing region (Matsumoto et al., 2019).

3.1. Anatomy of subiculum

3.1.1. Structure and cell architecture

The subiculum is comprised of three distinct layers, arranged from outermost to innermost: the molecular layer, the pyramidal cell layer, and the polymorphic layer (O'Mara et al., 2001; O'Mara, 2005). Despite its adjacency to sector CA1, the subiculum exhibits distinct molecular profiles. Studies demonstrate a clear cytoarchitectural boundary between the subiculum and CA1, underscoring their separate molecular organizations. Some molecular biomarkers, such as fibronectin1 and SMI-32, are used to differentiate subiculum from CA1 (Lein et al., 2004) or subregions within the subicular complex, respectively (Ding, 2013). Traditionally, the subiculum was not extensively divided and was roughly segmented into proximal and distal subiculum, based on its proximity to CA1 (Fujise et al., 1995; Ishihara and Fukuda, 2016), or along the dorso-ventral axis into dorsal and ventral subiculum (Fei et al., 2021). Using single-cell RNA sequencing along the dorso-ventral axis, 27 distinct transcriptomic cell types were identified in subiculum (and prosubiculum) (Ding et al., 2020).
The predominant neuronal population in the subiculum consists of principal pyramidal neurons, which release glutamate as their neurotransmitter. These pyramidal neurons are regulated by various GABAergic interneurons. Most pyramidal cells in the subiculum have a primary apical dendrite that is innervated by the hippocampus through the molecular layer, and they also possess axonal collaterals that are entering the alveus (Harris et al., 2001). Varicosities and axonal extensions within the pyramidal cell layer and apical dendritic region suggest intrinsic connectivity, while the presence of these features on axons projecting to the presubiculum, entorhinal cortex (EC), or CA1 classifies them as projection cells (Harris et al., 2001). Pyramidal cells of the subiculum can be categorized into two main groups: bursting neurons and regular spiking neurons (Böhm et al., 2015).
Within the subiculum, GABAergic interneurons form intricate circuits, including feedforward, feedback, and disinhibitory connections. The three primary subclasses of subicular interneurons (INs) expressing PV (PV-INs), SOM (SOM-INs), or vasoactive intestinal peptide (VIP-INs) (Kepecs and Fishell, 2014), play potentially opposing roles in subicular circuits. PV-INs, referred to as fast-spiking INs, represent the most abundant population of GABAergic neurons in the subiculum and are primarily located within the pyramidal cell layer (Fei et al., 2021). The majority of SOM-INs in the subiculum are regular spiking neurons, including bistratified cells and oriens-lacunosum moleculare (O-LM) interneurons (Pelkey et al., 2017). O-LM-INs, primarily located in the polymorphic layer, co-express nicotinic acetylcholine receptor alpha2 subunits (Leão et al., 2012; Nichol et al., 2018) and play a pivotal role in the subicular feedback inhibitory circuit (Pelkey et al., 2017). VIP-INs, originating from the caudal ganglionic eminence (Miyoshi et al., 2015), exhibit firing patterns that can be irregular, bursting, or stuttering (Pelkey et al., 2017). These VIP-INs often co-express calretinin and are key participants in the subiculum's disinhibitory circuitry (Rahimi et al., 2023). A recent finding identified a new group of VIP-INs that co-express muscarinic receptor 2 (M2R) and project from CA1 to subiculum (Luo et al., 2019). Unlike GABAergic neurons of the hippocampus (Klausberger and Somogyi, 2008), VIP interneurons of the subiculum exhibit higher activity levels during quiet wakefulness (Luo et al., 2019). Although GABAergic interneurons constitute only 10% to 15% of the total neuronal population in the hippocampus (Bezaire and Soltesz, 2013), their extensive anatomical and physiological diversity enables them to exert significant regulatory control over nearly all aspects of cellular and circuit functions in the subiculum (Pelkey et al., 2017).

3.1.2. The primary afferent and efferent connections of the subiculum

The subiculum receives its primary input from two critical regions, namely the CA1 region and the EC (O'Mara, 2005; Witter, 2006). Notably, pyramidal neurons located in the proximal CA1, close to sector CA2, innervate the distal subiculum (adjacent to the presubiculum), while pyramidal neurons of the distal CA1 innervate the proximal portion of the subiculum close to sector CA1 (Matsumoto et al., 2019). Cells in layer III of the lateral and medial EC (LEC and MEC) mainly terminate in the stratum lacunosum-moleculare of area CA1 and the molecular layer of the subiculum (Witter et al., 2000).
While there is accumulating evidence indicating that the subiculum also sends backward projections to sector CA1, the major outputs from the subiculum are directed towards the EC, exhibiting a precise spatial organization. The proximal half of the dorsal subiculum innervates the LEC, whereas the distal part is connected to the MEC (Witter, 2006). Projections from the ventral hippocampus target both the dorsal and ventral MEC (Ohara et al., 2023). Additionally, the ventral subiculum is composed of multiple distinct neuronal populations that send parallel, long-range projections to various areas, including the prefrontal cortex, nucleus accumbens shell (Wee and MacAskill, 2020), amygdalohippocampal area, antero-dorsal thalamic nucleus, medial hypothalamus (Tang et al., 2016) and several brain regions involved in sleep regulation, which will be elaborated upon Section 3.3.

3.2. The principal function of the subiculum

Lesioning the subiculum while minimizing damage to the adjacent hippocampal regions presents technical challenges. A pioneering study of Hagan and colleagues in 1992 was among the first to investigate the role of the subiculum in spatial navigation (Hagan et al., 1992). Through bilateral ibotenic acid injections in rats, they induced lesions encompassing the EC and subiculum. These rats exhibited impaired exploration, as evidenced by reduced motility and rearing in an open field arena. This observation has been subsequently confirmed by several other studies. The subiculum receives inputs from grid cells located in the MEC and place cells from the CA1 area of the hippocampus (Brotons-Mas et al., 2017). Dorsal subiculum neurons demonstrate a noise-resistant representation of place, speed, and trajectory, often as accurate as or more accurate than hippocampal CA1 neurons (Kitanishi et al., 2021). Additionally, it has been found that the activity of the ventral subiculum-ventral striatum pathway after learning is crucial for spatial memory consolidation and learning-induced plasticity (Torromino et al., 2019).
In addition to its role in spatial memory consolidation, which is dependent on specific tasks and training (Contreras et al., 2018), the ventral subiculum has been extensively studied for its involvement in contextual memory, reward and motivation processing, emotional regulation, and the stress response. For instance, the ventral subiculum has been implicated in the context-dependent renewal of extinguished Pavlovian conditioned responding to food cues (Anderson and Petrovich, 2017). Electrical stimulation of this region has been shown to reinvigorate behavior after the failure to achieve a goal in a food reward paradigm (Lindenbach et al., 2019). Ventral subicular lesion have been found to impair pro-social empathy-like behavior in adult Wistar rats (Subhadeep et al., 2022). Optogenetic activation of the circuit from the ventral subiculum to the ventral lateral septum triggers delayed but robust excessive grooming patterns, closely resembling those evoked by emotional stress (Mu et al., 2020). A direct circuit from the ventral subiculum to the anterior hypothalamic nucleus has been identified as essential for anxiety-like behavioral avoidance (Yan et al., 2022).
It is important to note that poor sleep quality can directly or indirectly affect all these primary functions of the subiculum. Recent research has indicated that sleep facilitates spatial memory (Simon et al., 2022) and poor sleep quality can impact spatial orientation (Valera et al., 2016), suggesting a potential alteration in subicular function. Insufficient sleep has been shown to affect how individuals learn from reward or punishment (Gerhardsson et al., 2021), and REMS deprivation can alter reward memory (Kaveh Shahveisi 2022). Interactions between insomnia, sleep duration and emotional processes have also been observed (Baglioni et al., 2023), and several studies in humans have linked fear and extinction recall/retention to both REMS and SWS (Bottary et al., 2023). However, it is crucial to recognize that various brain regions participate in the execution of these cognitive functions. Consequently, further research is necessary to explore whether the literature suggests anatomical and/or functional connections between the subiculum and sleep-wake behavior.

3.3. The anatomical connections between the subiculum and sleep-wake regulating areas

The anatomical connections of the subiculum with various brain areas involved in sleep-wake regulation have been comprehensively explored, as summarized in Table 1 and illustrated in Figure 3. These connections provide insights into the potential involvement of the subiculum in sleep-wake regulation.
1. MnPO: The temporal two-thirds of the subiculum are connected to the MnPO, as confirmed by anterograde Phaseolus vulgaris leucoagglutinin (PHA-L) and retrograde cholera toxin B subunit (CTB) injections (Kishi et al., 2000). Additionally, the ventral subiculum’s connection to the MnPO was identified using wheat germ agglutinin (Chiba and Murata, 1985) and pseudorabies virus injections (Westerhaus and Loewy, 1999). Furthermore, employing retrograde and anterograde axonal transport techniques (utilizing true blue, SITS, or wheat germ agglutinin), the MnPO displayed connections with the ventral subiculum (Simerly and Swanson, 1986).
2. VLPO: A direct connection between the VLPO and the ventral subiculum was described using retrograde tracer CTB subunit (Chou et al., 2002).
3. Hypothalamus: The ventral subiculum was found to have connections with various hypothalamic regions, including the anterior, tuberal, and mammillary regions, established through anterograde PHA-L and retrograde CTB subunit tracings (Kishi et al., 2000).
4. LH: Connections between the LH and the ventral subiculum were indicated by retrograde labelling through CTB-488 microinjections (Mu et al., 2020) , rabies virus injections (Shien Wee and MacAskill, 2021), and anterograde PHA-L tract-tracing (Köhler, 1990).
5. BF: Anterograde PHA-L tract-tracing provided evidence of connections between the subiculum and the BF (Yu et al., 2023).
6. VTA: The VTA exhibited disynaptic connections to the ventral subiculum, as demonstrated by anterograde PHA-L and retrograde CTB tracing techniques (Glangetas et al., 2015) and anterograde transsynaptic tracing using adeno-associated virus serotype 1 (Umaba et al., 2021).
7. LC: While some authors found a monosynaptic connection between the LC and the subiculum using uptake labeling and radioautography (Oleskevich et al., 1989), along with retrograde transport of horseradish peroxidase (Loy et al., 1980; Segal and Landis, 1974), others claimed second-order synapses (from the ventral subiculum, using herpes simplex virus 1 tracing technique) (Tang et al., 2016).
8. MRN: The medial part of the raphe nucleus was found to be connected to the ventral subiculum, as identified through Herpes simplex virus 1 tracing (Tang et al., 2016).
9. LDT: Using the Herpes simplex virus 1 tracing technique, connections between the LDT and the ventral subiculum were identified (Tang et al., 2016).
10. SCN: The SCN displayed connections with the ventral subiculum, as revealed through retrograde CTB tracing (Krout et al., 2002).
These findings provide insight into the intricate connection of the subiculum, particularly ventral subiculum, to sleep-wake promoting areas, hinting at its potential involvement in regulating sleep and wakefulness.

3.4. Clinical studies

Structural changes in the subiculum have been observed in patients with sleep disorders, specifically Obstructive Sleep Apnea (OSA). Macey et al. collected high-resolution magnetic resonance imaging (MRI) images from 66 newly-diagnosed, untreated OSA patients (mean age ± SD: 46.3 ± 8.8 years; 50 males) and 59 healthy age-matched control participants (46.8 ± 9.0 years; 38 males) (Macey et al., 2018). Male patients exhibited higher bilateral volume throughout CA1 and subiculum, with greater right-hemispheric increases and lower bilateral volumes in the mid- and posterior-CA3/DG. Female patients showed right-hemispheric differences with increased volumes in CA1 and the subiculum/uncus, and decreased volumes in the posterior CA3/DG (Figure 4).
Lee et al. calculated cortical thickness and hippocampal subfield volumes from images of 45 controls (age 15.43 ± 1.73 years, 21 males) and 53 adolescent children with OSA (age 15.26 ± 1.63 years, 32 males) to investigate the association of childhood OSA with alterations in cortical structure and hippocampal subfield structural changes (Lee et al., 2023). They observed that in adolescents with OSA, only the volume of the right-hemispheric subiculum-head area of the hippocampus was larger compared to the control group. This enlargement was positively correlated with both the apnea-hypopnea index (AHI) and the arousal index.
Recently, the association of sleep-disorder-related breathing impairments and medial temporal lobe atrophy in cognitively unimpaired amyloid-positive older adults was assessed (André et al., 2023). Data were collected between 2016 and 2020 as part of the Age-Well randomized controlled trial conducted under the Medit-Ageing European project. The AHI interacted with the volumes of the EC, subiculum, CA1, and DG. This interaction revealed that in individuals with amyloid-positive status, higher severity of sleep apnea was associated with reduced volumes of sub-regions in the medial temporal lobe. Notably, this relationship did not hold true for individuals who were amyloid-negative.
Subicular volume changes were also reported in connection with other sleep impairments. To assess the relationship between sleep duration, sleep impairments, perceived stress, and hippocampal subfield volumes in later life, adults (aged 68.8 ± 7.3; 46% males) from the Irish Longitudinal Study on Ageing completed a questionnaire along with multiparametric brain MRI (Looze et al., 2022). No cross-sectional and follow-up associations between sleep and total hippocampal volume, and between stress and total hippocampal volume, were found. In contrast, long sleep duration (≥9-10 hours per night) was linked to smaller volumes of the molecular layer, hippocampal tail, presubiculum, and subiculum. On the other hand, the combination of short sleep duration (≤6 hours) and higher perceived stress was associated with smaller volumes of CA1, molecular layer, subiculum, and hippocampal tail. Sleep impairments, independently and in conjunction with higher stress, together with the severity of sleep impairments were associated with smaller volumes of these same subfields. Similarly, Liu et al. reported that poor sleep was associated with smaller hippocampal subfields in healthy elderly individuals (Liu et al., 2021). Sleep quality was self-assessed using the Pittsburgh Sleep Quality Index (PSQI), and hippocampal volumes were measured from MRI data. A total of 67 cognitively normal elderly individuals aged 60-83 years were classified into 30 normal sleepers with a PSQI <5 and 37 poor sleepers with a PSQI ≥5. Compared to normal sleepers, poor sleepers exhibited significantly lower normalized volumes in the left CA1, DG, and subiculum, and the global PSQI was negatively associated with the normalized volumes of these regions (only in the left hemisphere).
Only one study assessed the changes in subiculum in connection to sleep in healthy individuals (Andrade et al., 2011). Young healthy subjects underwent simultaneous EEG and functional MRI measurements under resting conditions during the descent to sleep stage N3. The hippocampal function was integrated to variable strength in the default mode network in wakefulness and sleep stage N1 but not in slow wave sleep (SWS). While the cornu ammonis exhibited the strongest functional connectivity with the default mode network during wakefulness, the subiculum dominated hippocampal functional connectivity to frontal brain regions during sleep stage N2.

3.5. Animal studies

The pioneering study by Hagan et al. in 1992 explored the role of the subiculum in spatial navigation and also reported changes in sleep behavior in rats (Hagan et al., 1992). Bilateral ibotenic acid injections induced lesions in the EC/subiculum, resulting in increased diurnal SWS and spindle incidence, along with decreased REMS. Additionally, there was a reduction in theta power during REMS and quiet waking, but not during SWS. Subsequent studies did not investigate the potential role of the subiculum/EC in sleep regulation. However, a systematic approach involving immediate-early gene mapping, laser microdissection, cDNA microarrays, and in situ hybridization revealed significant molecular changes in the subiculum after 6 hours of sleep deprivation (Thompson et al., 2010), highlighting neuronal interactions between the subiculum and sleep. Additionally, observations indicated that a substantial set of genes and proteins in the ventral hippocampus (containing the ventral subiculum) exhibited circadian oscillations in healthy mice, which could influence various circadian rhythms in the brain (Debski et al., 2020). Despite the limited exploration of the direct relationship between the subiculum and sleep-wake behavior, the role of the subiculum in generating sleep oscillations has been well discussed.
Ibotenic acid lesioning of the ventral subiculum increased the absolute theta power in the CA1 area, with no noticeable change in its relative power (Laxmi et al., 2000). Conversely, this lesioning led to a decrease in both the absolute and relative power of EC theta power, indicating that the subicular output may play a modulatory role in the synchronous neuronal activity of EC and CA1-pyramidal cells during REMS. Bandarabadi et al. explored the dynamics of theta-gamma band interactions, utilizing multiple frequency and temporal scales during simultaneous recordings from hippocampal CA3, CA1, subiculum, and parietal cortex in freely moving mice (Bandarabadi et al., 2019). Interestingly, they found that coupling during REMS was significantly stronger than during active wake within the subiculum and parietal cortex, but no such differences were observed within CA3 and CA1. The theta power exhibited no significant changes across REMS, except within the subiculum with notable alterations. Additionally, the theta phase significantly modulated the ultrahigh gamma band (160-250 Hz) in pyramidal cell layers of CA3 and the subiculum exclusively. It was suggested that the role of the subiculum in theta- and gamma oscillations is modulated by cholinergic inputs to the ventral subiculum, as the elimination of these inputs significantly reduced subicular theta- and enhanced gamma activity during active wake and REMS states (Rastogi et al., 2014). Intriguingly, an autoradiographic study revealed that after 96 hours of REMS deprivation, a decrease in muscarinic receptor binding in the EC and subiculum could be recorded, but not in other parts of the hippocampal formation (Nunes et al., 1994).
Recent work by Raquet et al. demonstrated that neonatal exposure to the novel sedative/hypnotic drug, 3β-OH, resulted in reduced subicular delta- and sigma band oscillations during NREMS (Fine-Raquet et al., 2023). In contrast, a previous study by the same authors found that neonatal exposure to the common anesthetic agent ketamine increased subicular gamma band oscillations during NREMS and significantly suppressed subicular long-term potentiation in adolescent rats (Manzella et al., 2020). These findings suggest that exposure to different sedative/hypnotic agents during a critical period of brain development may induce distinct functional changes in subiculum circuitry that persist into adolescence. Recently, through anatomically restricted inactivation of VIP-INs in the ventral subiculum of epileptic mice, we observed a significant shift in the circadian rhythm of seizures (Rahimi et al., 2023), implying a prominent interaction between the ventral subiculum and circadian rhythm. However, the epileptic brain exhibits distinct functional connectivity compared to a non-epileptic one (Morgan et al., 2015); therefore, in-depth studies in normal behaving animals are essential to reveal the complexities and mechanisms underlying this relationship.

4. Conclusions and perspectives

The subiculum presents an enticing area for future research endeavors. Investigations on the precise neurophysiological mechanisms governing the subiculum's interactions with sleep-regulatory regions, as well as the molecular and cellular processes occurring within the subiculum during sleep-wake transitions, hold the promise of deeper insights into sleep neurobiology. In addition, pharmacological and neuromodulatory interventions targeting this region may offer innovative approaches to ameliorate sleep disorders and enhance overall sleep quality.
In conclusion, the subiculum might emerge as a pivotal, yet understudied player in the neural orchestration of sleep-wake behavior. Its complexity and clinical implications beckon for continued scientific inquiry. As we advance our understanding of this brain region, we may gain a more profound understanding of the fundamental processes governing sleep.

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Figure 1. Similarities and differences in sleep and wake patterns between mice and humans. (A) Representative EEG (Electroencephalogram), its density spectral array (DSA), and corresponding EMG (Electromyogram) recordings from a mouse during Wake, NREMS (Non-Rapid Eye Movement Sleep), and REMS (Rapid Eye Movement Sleep). The mouse EEG signals were amplified 1000 times before digitization. Notably, during REMS, theta frequency power is significantly higher compared to NREMS and Wake, as indicated in the DSA. (B) Color-coded brain states (hypnogram) during a continuous 23-hour recording from a mouse under a light-dark cycle. Mice, being nocturnal animals, tend to sleep more during the light cycle. Their sleep patterns are characterized by fragmented sleep, featuring short sleep bouts and frequent awakenings. (C) Examples of a human EEG, its DSA, and corresponding EMG recordings during Wake, NREMS (stage 3), and REMS. REMS exhibits desynchronized rhythms similar to Wake but can be distinguished by EMG activity. (D) Color-coded brain states (hypnogram) during a continuous 23-hour recording from a healthy human subject. In humans, sleep is typically consolidated with rare awakenings during the night. REMS sleep occurs regularly approximately every 90 minutes.
Figure 1. Similarities and differences in sleep and wake patterns between mice and humans. (A) Representative EEG (Electroencephalogram), its density spectral array (DSA), and corresponding EMG (Electromyogram) recordings from a mouse during Wake, NREMS (Non-Rapid Eye Movement Sleep), and REMS (Rapid Eye Movement Sleep). The mouse EEG signals were amplified 1000 times before digitization. Notably, during REMS, theta frequency power is significantly higher compared to NREMS and Wake, as indicated in the DSA. (B) Color-coded brain states (hypnogram) during a continuous 23-hour recording from a mouse under a light-dark cycle. Mice, being nocturnal animals, tend to sleep more during the light cycle. Their sleep patterns are characterized by fragmented sleep, featuring short sleep bouts and frequent awakenings. (C) Examples of a human EEG, its DSA, and corresponding EMG recordings during Wake, NREMS (stage 3), and REMS. REMS exhibits desynchronized rhythms similar to Wake but can be distinguished by EMG activity. (D) Color-coded brain states (hypnogram) during a continuous 23-hour recording from a healthy human subject. In humans, sleep is typically consolidated with rare awakenings during the night. REMS sleep occurs regularly approximately every 90 minutes.
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Figure 2. Brain circuit involved in (A) Wake (B) NREMS, and (C) REMS. The depicted brain regions are intricately connected and can serve dual roles in both promoting sleep and maintaining wakefulness. Certain medulla oblongata nuclei, such as the Dorsal Paragigantocellular Nucleus, Lateral Paragigantocellular Nucleus, Gigantocellular Nucleus, and Gigantocellular Nucleus Alpha, along with components of the peripheral nervous system like premotor neurons and spinal motor neurons, contribute to motor inhibition during REMS. However, these elements have been excluded from (C) for the sake of this review’s focus. The figure is partially adopted from Scammell et al. (Scammell et al., 2017) and has undergone extensive modifications.
Figure 2. Brain circuit involved in (A) Wake (B) NREMS, and (C) REMS. The depicted brain regions are intricately connected and can serve dual roles in both promoting sleep and maintaining wakefulness. Certain medulla oblongata nuclei, such as the Dorsal Paragigantocellular Nucleus, Lateral Paragigantocellular Nucleus, Gigantocellular Nucleus, and Gigantocellular Nucleus Alpha, along with components of the peripheral nervous system like premotor neurons and spinal motor neurons, contribute to motor inhibition during REMS. However, these elements have been excluded from (C) for the sake of this review’s focus. The figure is partially adopted from Scammell et al. (Scammell et al., 2017) and has undergone extensive modifications.
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Figure 3. Three-dimensional (3D) reconstruction and the schematic connections of the subiculum to the brain areas involved in the regulation of vigilance states. In the 3D reconstruction, the subiculum (Sub) is highlighted by red color. Disynaptic connection is shown by sign. BF: Basal Forebrain; LC: Locus Coeruleus; LH: Lateral Hypothalamus; LDT: Laterodorsal Tegmentum; MRN: Median Raphe Nucleus; SCN: Suprachiasmatic Nucleus; SLD: Sub-Laterodorsal (Tegmental) Nucleus; TMN: Tuberomammillary Nucleus; VTA: Ventral Tegmental Area.
Figure 3. Three-dimensional (3D) reconstruction and the schematic connections of the subiculum to the brain areas involved in the regulation of vigilance states. In the 3D reconstruction, the subiculum (Sub) is highlighted by red color. Disynaptic connection is shown by sign. BF: Basal Forebrain; LC: Locus Coeruleus; LH: Lateral Hypothalamus; LDT: Laterodorsal Tegmentum; MRN: Median Raphe Nucleus; SCN: Suprachiasmatic Nucleus; SLD: Sub-Laterodorsal (Tegmental) Nucleus; TMN: Tuberomammillary Nucleus; VTA: Ventral Tegmental Area.
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Figure 4. Hippocampal volume changes in female with obstructive sleep apnea (OSA) relative to controls, with age and total intracranial volume (TIV) as covariates (adopted from Macey et al. (Macey et al., 2018)). Interestingly, in female patients, subiculum/uncus showed the most significant alternation in comparison to other regions of the hippocampal formation.
Figure 4. Hippocampal volume changes in female with obstructive sleep apnea (OSA) relative to controls, with age and total intracranial volume (TIV) as covariates (adopted from Macey et al. (Macey et al., 2018)). Interestingly, in female patients, subiculum/uncus showed the most significant alternation in comparison to other regions of the hippocampal formation.
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Table 1. Neuronal connectivity between the subiculum and sleep-wake promoting areas.
Table 1. Neuronal connectivity between the subiculum and sleep-wake promoting areas.
Species Which region of subiculum Which area Which technique Monosynaptic or disynaptic Reference
rat temporal two-thirds medial preoptic region anterograde Phaseolus vulgaris leucoagglutinin (PHA-L) and retrograde cholera toxin B subunit monosynaptic (Kishi et al., 2000)
rat Not specified MnPO wheat germ agglutinin conjugated to horseradish peroxidase monosynaptic (Chiba and Murata, 1985)
rat ventral MnPO pseudorabies virus injections monosynaptic (Westerhaus and Loewy, 1999)
rat ventral MnPO retrograde and anterograde axonal transport techniques (true blue, SITS, or wheat germ agglutinin) monosynaptic (Simerly and Swanson, 1986)
rat ventral VLPO retrograde tracer CTB subunit monosynaptic (Chou et al., 2002)
rat full longitudinal extent anterior, tuberal, and mammillary regions of hypothalamus anterograde Phaseolus vulgaris leucoagglutinin (PHA-L) and retrograde cholera toxin B (CTB) subunit monosynaptic (Kishi et al., 2000)
rat ventral LH Retrograde labelling by CTB-488 microinjection monosynaptic (Mu et al., 2020)
mouse ventral LH Rabies virus injection monosynaptic (Shien Wee and MacAskill, 2021)
rat ventral LH anterograde PHA-L tract-tracing method monosynaptic (Köhler, 1990)
mouse ventral BF retrograde and anterograde virus tracing method monosynaptic (Yu et al., 2023)
mouse ventral VTA anterograde PHA-L and retrograde CTB disynaptic (through BNST) (Glangetas et al., 2015)
rat dorsal VTA anterograde transsynaptic tracing using adeno-associated virus serotype 1 disynaptic (through medial mammillary nucleus) (Umaba et al., 2021)
rat Not specified LC Uptake labeling and radioautography monosynaptic (Oleskevich et al., 1989)
rat Not specified LC retrograde transport of horseradish peroxidase monosynaptic (Loy et al., 1980)
rat Not specified LC retrograde transport of horseradish peroxidase monosynaptic (Segal and Landis, 1974)
mouse ventral LC Herpes simplex virus 1 strain H129 with an inserted fluorescent protein gene disynaptic (Tang et al., 2016)
mouse ventral MRN Herpes simplex virus 1 strain H129 with an inserted fluorescent protein gene disynaptic (Tang et al., 2016)
mouse ventral LDT Herpes simplex virus 1 strain H129 with an inserted fluorescent protein gene monosynaptic (Tang et al., 2016)
rat ventral SCN retrograde CTB monosynaptic (Krout et al., 2002)
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