Chapter 8 - Importance of the ventral midline thalamus in driving hippocampal functions

https://doi.org/10.1016/bs.pbr.2015.03.005Get rights and content

Abstract

The ventral midline of the thalamus encompasses the reuniens and rhomboid (ReRh) nuclei. These nuclei are bidirectionally connected with the hippocampus and the medial prefrontal cortex (mPFC). About 8% of the neurons of the Re have collaterals in both structures. The ReRh nuclei provide the major thalamic input to the hippocampus. Their stimulation induces long-term potentiation in region CA1, suggesting a role in hippocampal plasticity. Experimental manipulations of the ReRh nuclei such as lesions, reversible inactivations, or optogenetic stimulations produce alterations of cognitive functions, especially in tasks known for their sensitivity to lesions of the hippocampus, but also of the mPFC. Behavioral approaches suggest that the ReRh nuclei might relay incoming signals from the mPFC both to the hippocampus and back to the mPFC. Thus, the Re and Rh nuclei have a role in orchestrating the information flow between the hippocampus and the mPFC, and this orchestration has both “online” and “off-line” implications in cognitive functions.

Introduction

Due to its anatomical proximity with the “smell brain” (rhinencephalon), the hippocampus was first thought to be a structure with olfactory functions (Brodal, 1947). Observations by Klüver and Bucy in primates with temporal lobe damage (1939) then involved it in emotions and affective responses. Later on, the dramatic consequences on memory of the ablation of Gustav Henry Molaison's medial temporal lobes contributed to make the hippocampus a structure of utmost importance for memory functions (Augustinack et al., 2014, Milner, 2005). Since the end of the 1950s, the hippocampus has been explored from all possible angles. Accumulating evidence has once and for all made it hardly dissociable from declarative-like memory functions: in humans, the hippocampus enables the consolidation of consciously encoded information and ensures the storage of recent memories and their conscious retrieval, while its implication in remote memories is still debated (e.g., Moscovitch et al., 2005). This debate is paralleled by its twin in rats and mice (e.g., Winocur et al., 2010). The hippocampus is also considered a central structure of episodic and even autobiographical memory (Eichenbaum et al., 2012, Maguire and Mullally, 2013), and it is inseparable from spatial representations and navigation processes (Hartley et al., 2013).

Supporting the latter point, the discovery in rats of neurons firing when the animal enters a particular place in the environment by John O’Keefe and Jonathan Dostrovsky at the beginning of the 1970s has pointed to a functional specialization of a subpopulation of hippocampal neurons called “place cells” (O'Keefe and Dostrovsky, 1971). Place cells participate in the construction and storage of maps of the environment in which evolved organisms navigate. They count as one of the neuronal substrates of spatial coding, in addition to grid, border (or boundary), and head direction cells (e.g., Hartley et al., 2013). In 2007, Eichenbaum and his group (Manns et al., 2007) provided the first evidence that the hippocampus bears neurons encoding time and these neurons can be the same as the place cells (Eichenbaum, 2014). The “time cells” most probably contribute to the processing of the temporal dimension of memories and enable their chronological organization along a temporal axis.

Just from these few examples, it becomes clear that the hippocampus is all but a single-task structure. Turning attention toward its connectivity brings another point to light: the hippocampus is not an isolated region, neither anatomically nor functionally. It is part of a large system encompassing many cortical and subcortical structures. The main cortical structure connected with the hippocampus is the entorhinal cortex. The hippocampus also sends projections to the prefrontal cortex, from which it does not receive direct feedback (e.g., Thierry et al., 2000). Subcortical inputs are from the amygdala, the thalamus (anterior and midline), the basal forebrain, the ventral tegmental area, the raphe nuclei, and the locus coeruleus. Subcortical outputs are to some of these regions (amygdala, septum, thalamus) plus the nucleus accumbens, hypothalamus, and mammillary nuclei (Amaral and Witter, 1995).

Regarding the thalamus, its anterior nuclei have received most attention over the past, perhaps especially because of the link between their damage in strokes or Korsakoff's syndrome and the diencephalic amnesia associated with these disorders (e.g., Aggleton and Nelson, 2015). In comparison, the midline thalamus, and therein the ventral midline nuclei, has been quite neglected. This ventral midline ensemble is made of two relatively small nuclei termed reuniens and rhomboid (ReRh) nuclei. The ReRh nuclei provide the major thalamic input to the hippocampus. Together with the intralaminar and dorsal midline nuclei, the ReRh nuclei belong to an entity that Lorente de No (1938) has named the nonspecific thalamus. This entity is characterized by sparse projections to multiple cortical regions, hence their presumed nonspecificity. Later on, electrophysiological arguments even provided further support to the specific/nonspecific dichotomy (for review, see Cassel et al., 2013, Pereira de Vasconcelos and Cassel, 2015). Interest in the functional contributions of the ReRh is relatively recent. In fact, it has increased over the last decade, among other reasons because the connectivity of these nuclei places them in a hub position between the hippocampus and the medial prefrontal cortex (mPFC; Hoover and Vertes, 2012, Varela et al., 2014). Therefore, the ReRh nuclei could be potential modulators of functions requiring cooperative information processing between the hippocampus and the mPFC. After a brief reminder of connectivity, we will review direct and indirect electrophysiological arguments indicating a possible contribution of ReRh neurons to hippocampal functioning and will then focus on consequences of functional manipulations of the ReRh, including permanent lesions, on tasks requiring the hippocampus in its relations with the mPFC.

Section snippets

Reuniens Nucleus

The Re receives afferents from/provides efferents to tel-, di-, mes-, met-, and myelencephalic structures, as synthetized in Table 1. The corresponding references and more detail can be found in Cassel et al. (2013). It is noteworthy that the projections from the Rh concentrate in a narrow band corresponding to the stratum lacunosum-moleculare of region CA1. There are no Re terminals in other hippocampal subregions (i.e., CA2, CA3, and dentate gyrus). Hippocampal afferents to the Re are from

Electrophysiology

Based on their connectivity, it seems reasonable to expect that changes in the activity of ReRh neurons should influence hippocampal activity and vice versa. To the best of our knowledge, there is no published experiment on the consequences of hippocampal activity stimulation or blockade on neuronal firing in the ReRh. Conversely, alterations of hippocampal activity following ReRh stimulation or blockade have been documented, although sparsely and for part rather indirectly.

Cognition

Some of the cognitive symptoms of patients suffering from Alzheimer's disease are characteristic of hippocampal dysfunctions. This is the case for working memory, episodic memory, and consolidation deficits. Interestingly, numerous neurofibrillary tangles, neuropil threads, and degeneration signs are found in the Re nucleus of Alzheimer's disease patients (Braak and Braak, 1991, Braak and Braak, 1998). Such coincidences, however, do not imply that the aforementioned deficits are a consequence

Discussion

The Re and Rh have strong bidirectional connections with the hippocampus, as is the case with the mPFC. Evidence—mainly from electrophysiological approaches—that these connections might influence hippocampal activity is both direct (e.g., Dolleman-van der Weel et al., 1997, Morales et al., 2007) and indirect (Jankowski et al., 2014). What happens in the hippocampus after ReRh lesions or inactivation remains poorly documented, but the finding that a stimulation of the Re induces long term

Conflict of Interest

The authors have no conflict of interest to declare.

Acknowledgments

The work performed in our laboratory and mentioned in this review was supported by the CNRS, the University of Strasbourg, the INSERM, and the ANR (ANR-14-CE13-0029-01). Special thanks go to all people who contributed to this research and cosigned our former publications on the functions of the ReRh. We also thank Ms. Delphine Cochand for editing the English language of this chapter.

References (50)

  • K. Otake et al.

    Single midline thalamic neurons projecting to both the ventral striatum and the prefrontal cortex in the rat

    Neuroscience

    (1998)
  • M.C. Porter et al.

    A comparison of the effects of hippocampal and prefrontal cortical lesions on three versions of delayed non-matching-to-sample based on positional or spatial cues

    Behav. Brain Res.

    (2000)
  • E.A. Scholl et al.

    Neuronal degeneration is observed in multiple regions outside the hippocampus after lithium pilocarpine-induced status epilepticus in the immature rat

    Neuroscience

    (2013)
  • G. Winocur et al.

    Memory formation and long-term retention in humans and animals: convergence towards a transformation account of hippocampal-neocortical interactions

    Neuropsychologia

    (2010)
  • J.P. Aggleton et al.

    Why do lesions in the rodent anterior thalamic nuclei cause such severe spatial deficits?

    Neurosci. Biobehav. Rev,

    (2015)
  • D.G. Amaral et al.

    Hippocampal formation

  • J.C. Augustinack et al.

    H.M.’s contributions to neuroscience: a review and autopsy studies

    Hippocampus

    (2014)
  • E.H. Bertram et al.

    The midline thalamus: alterations and a potential role in limbic epilepsy

    Epilepsia

    (2001)
  • H. Braak et al.

    Alzheimer's disease affects limbic nuclei of the thalamus

    Acta Neuropathol.

    (1991)
  • H. Braak et al.

    Evolution of neuronal changes in the course of Alzheimer's disease

    J. Neural Transm. Suppl.

    (1998)
  • M.P. Brandon et al.

    Parallel and convergent processing in grid cell, head-direction cell, boundary cell, and place cell networks

    Wiley Interdiscip. Rev. Cogn. Sci.

    (2014)
  • A. Brodal

    The hippocampus and the sense of smell: a review

    Brain

    (1947)
  • T. Cholvin et al.

    The ventral midline thalamus contributes to strategy shifting in a memory task requiring both prefrontal cortical and hippocampal functions

    J. Neurosci.

    (2013)
  • B.J. Clark et al.

    Vestibular and attractor network basis of the head direction cell signal in subcortical circuits

    Front. Neural Circuits

    (2012)
  • M.J. Dolleman-van der Weel et al.

    Reuniens nucleus thalami modulates activity in hippocampal field CA1 through excitatory and inhibitory mechanisms

    J. Neurosci.

    (1997)
  • Cited by (26)

    • A Visual Circuit Related to the Nucleus Reuniens for the Spatial-Memory-Promoting Effects of Light Treatment

      2021, Neuron
      Citation Excerpt :

      The nucleus reuniens (Re) of the midline thalamus is highly conserved across species and is interconnected with the limbic systems, including the hippocampus (HPC) (Wouterlood et al., 1990; Vertes et al., 2006; Hoover and Vertes 2012; Cassel et al., 2013; Varela et al., 2014). Accumulating evidence suggest that the Re contributes to the regulation of neuronal activity in the HPC and plays a prominent role in memory processing (Loureiro et al., 2012; Cassel and Pereira de Vasconcelos, 2015; Cholvin et al., 2018; Jung et al., 2019; Hauer et al., 2019; Klein et al., 2019). Notably, the Re is a target of multiple cortical and subcortical brain regions that appears to receive sensory input via different modalities (McKenna and Vertes, 2004; Oh et al., 2014; Scheel et al., 2020), and neuronal activity in the Re can be regulated by bright light (Brown et al., 2011).

    • A thalamic bridge from sensory perception to cognition

      2021, Neuroscience and Biobehavioral Reviews
    • Single-day Postnatal Alcohol Exposure Induces Apoptotic Cell Death and Causes long-term Neuron Loss in Rodent Thalamic Nucleus Reuniens

      2020, Neuroscience
      Citation Excerpt :

      While the period of developmental neurogenesis ends in Re around embryonic day 17, our data assess total cell number, suggesting that glial cells are also present at their adult numbers by the second week of postnatal life. We propose that Re—the most direct and prominent pathway for information transfer from mPFC to HPC (Cassel and Pereira de Vasconcelos 2015) which remains understudied in the context of neurodevelopmental disorders—is more sensitive than previously expected to alcohol-induced damage in early postnatal life. Gursky et al. (2019) previously identified that neuron loss following multiple days of AE was selective to Re (i.e., was not present in the adjacent rhomboid nucleus of ventral midline thalamus).

    • Impaired hippocampus-dependent associative learning as a mechanism underlying PTSD: A meta-analysis

      2019, Neuroscience and Biobehavioral Reviews
      Citation Excerpt :

      While the hippocampus and PFC are both involved in early memory consolidation and retrieval (i.e., in the first few hours after learning), the PFC is primarily involved in late memory consolidation and retrieval (i.e., hours to weeks after learning) (for a review, see Euston et al., 2012). The midline thalamus (i.e., rhomboid and reuniens nuclei) connects the hippocampus and mPFC and is particularly relevant for functions involving both the hippocampus and mPFC, including transferring recent memories to remote memories (Cassel and de Vasconcelos, 2015; Vertes, 2006). We do not focus on amygdala-mediated associative learning of cues during fear conditioning or extinction learning.

    • Aberrant Network Activity in Schizophrenia

      2017, Trends in Neurosciences
      Citation Excerpt :

      This enhanced, and persistent connectivity correlates with enhanced thalamic delta rhythm generation via a predominantly NR2C receptor subunit-dependent mechanism (reviewed in [74]). Thus, the balance between the two key prefrontal-hippocampal pathways may be biased away from the theta rhythm-coordinated direct pathway vital for sequential memory, which is reduced in animal models [75], and towards the indirect pathway via thalamic nucleus reuniens [76], coordinated at the slower delta frequency. Working memory maintenance is dependent on theta-frequency fluctuations in hippocampal activity; thus, replacement of this temporal signature with the slower delta rhythm may underlie the prolonged temporal discrimination window seen in patients [77].

    View all citing articles on Scopus
    View full text