A conductor hidden in the orchestra? Role of the habenular complex in monoamine transmission and cognition

doi:10.1016/j.neubiorev.2007.01.004

Neuroscience & Biobehavioral Reviews

Volume 31, Issue 5, 2007, Pages 658-672

https://doi.org/10.1016/j.neubiorev.2007.01.004 Get rights and content

Abstract

Influences of the habenular complex on electrophysiological and neurochemical aspects of brain functioning are well known. However, its role in cognition has been sparsely investigated until recently. The habenular complex, composed of medial and lateral subdivisions, is a node linking the forebrain with midbrain and hindbrain structures. The lateral habenula is the principal actor in this direct dialogue, while the medial habenula mostly conveys information to the interpeduncular nucleus before this modulates further regions. Here we describe neuroanatomical and physiological aspects of the habenular complex, and its role in cognitive processes, including new behavioral, electrophysiological and imaging findings. Habenular complex lesions result in deficits in learning, memory and attention, some of which decline during repeated testing, while others become worse, consistent with multiple roles in cognition. The habenular complex is particularly responsive to feedback about errors. Electrophysiological studies indicate a role in metaplasticity, the modulation of neuroplasticity. These studies thus reveal important roles of the habenular complex in learning, memory and attention.

Introduction

In the last two decades several studies in the rat and the cat revealed that the habenular complex (HbCpl), an epithalamic structure, is involved in the regulation of ascending monoamine and acetylcholine transmission, and represents a key link between the forebrain and midbrain and hindbrain areas. Because of this role in monoamine regulation, and because chronic treatment with amphetamine or cocaine causes psychosis-like symptoms in man and specific degeneration of the HbCpl in rats (Ellison, 1992, Ellison, 2002; Ellison and Switzer 1993), it was hypothesized that the HbCpl is involved in pathologies such as schizophrenia or hypersensitivity to stress. Although a small number of imaging studies (Sandyk, 1992; Caputo et al., 1998) showed alterations of the HbCpl in schizophrenic patients compared to healthy individuals, until recently only very few attempts had been made in preclinical or in clinical research to test this hypothesis.

In this review we first present an overview of the connections that the HbCpl shares with extrapyramidal and limbic structures, as well as detailed mechanisms by which it influences ascending monoamine and acetylcholine transmission. Then, based particularly on experiments performed in the past few years, we emphasize the role of the HbCpl in cognitive behaviors, such as learning, memory and attention. Consistent with previous hypotheses (Sandyk, 1991; Ellison, 1994; Kelly, 1998) the results, obtained by us and other groups, clearly suggest that a defective HbCpl is involved in the cognitive deficits of schizophrenia, and also induces vulnerability to stress, a well-known precipitating factor.

Section snippets

Anatomy and connections of the habenular complex

The HbCpl is a diencephalic structure located on the dorsomedial surface of the caudal thalamus. Together with the pineal gland, it is said to form the epithalamus. The neuroanatomy of the HbCpl has been best studied in the rat. It consists of two distinct nuclei, the medial (MHb) and the lateral (LHb) habenular nucleus (Gurdjian, 1925), the former being composed of 5 sub-nuclei and the latter of 10 sub-nuclei (Andres et al., 1999; Geisler et al., 2003). MHb and LHb are very distinct from one

Role of the habenular complex in cognition

Consistent with its widespread regulatory role upon monoamine transmission towards various key structures of the forebrain, the HbCpl exerts considerable influence upon many behaviors (see reviews, Klemm, 2004; Sutherland, 1982). These include the regulation of sleep (Haun et al., 1992; Valjakka et al., 1998), reward (Sutherland and Nakajima, 1981; Waraczynski, 2006), pain (Benabid and Jeaugey, 1989; Cohen and Melzack, 1985; Smith et al., 1997), sexual (Modianos et al., 1974; Tennent et al.,

Conclusion

The HbCpl is a node of a reciprocal route of communication between the limbic and extrapyramidal systems. Its inputs arise from limbic and basal ganglia regions of the forebrain including the lateral hypothalamus, all septal regions which relay information from the hippocampus, the preoptic area and the entopeduncular nucleus. The HbCpl has been clearly shown to participate in the regulation of monoaminergic transmission, serotonergic, dopaminergic and noradrenergic, as well as cholinergic

Future directions

Considering the anatomical and neurochemical complexity of the HbCpl, much work remains to unfold the details of how this intriguing structure exerts its multiple effects on behavior, and to determine if and how its disturbance contributes to disorders such as schizophrenia. For example, it seems necessary to investigate specifically the role of the MHb in monoamine transmission by combining specific lesions or localized stimulation with microdialysis studies. Also, the impact of HbCpl lesion

Acknowledgments

The authors gratefully acknowledge Drs. Mark E. Jackson, Laura Jacobson and John F. Cryan for very helpful comments on the manuscript.

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ReviewA conductor hidden in the orchestra? Role of the habenular complex in monoamine transmission and cognition

Abstract

Introduction

Section snippets

Anatomy and connections of the habenular complex

Role of the habenular complex in cognition

Conclusion

Future directions

Acknowledgments

Brain Research

Brain Research

Brain Research

Brain Research

Neuroscience Letters

Behavioural Brain Research

Brain Research

Neuroscience

Neurochemistry International

Behavioural Brain Research

Brain Research

Brain Research

Neuroscience

Molecular Brain Research

Brain Research

Brain Research

Brain Research Review

European Neuropsychopharmacology

Trends in Neurosciences

Brain Research

Brain Research

Brain Research

Brain Research

Brain Research

Behavioral Brain Research

Brain Research Bulletin

Brain Research

Brain Research

Neuropharmacology

Neuroscience Letters

Brain Research Bulletin

Neuroscience

Neuroscience

Molecular Cells

Brain Research

Brain Research

Brain Research

Behavioral Biology

Brain Research

Brain Research Bulletin

Neuroscience

Neuron

Behavioral Brain Research

Brain Research

Neuroscience

Brain Research

Subnuclear organization of the rat habenular complexes

Journal of Comparative Neurology

Substance P in the interpeduncular nucleus of the rat: normal distribution and the effects of deafferentation

Journal of Comparative Neurology

Bilateral lesions of the subthalamic nucleus induce multiple deficits in an attentional task in rats

European Journal of Neuroscience

Enhanced inhibition of synaptic transmission by dopamine in the nucleus accumbens during behavioral sensitization to cocaine

Journal of Neuroscience

Review
A conductor hidden in the orchestra? Role of the habenular complex in monoamine transmission and cognition