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Review
, 81 (4), 296-305

Translating the Habenula-From Rodents to Humans

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Review

Translating the Habenula-From Rodents to Humans

Laura-Joy Boulos et al. Biol Psychiatry.

Abstract

The habenula (Hb) is a central structure connecting forebrain to midbrain regions. This microstructure regulates monoaminergic systems, notably dopamine and serotonin, and integrates cognitive with emotional and sensory processing. Early preclinical data have described Hb as a brain nucleus activated in anticipation of aversive outcomes. Evidence has now accumulated to show that the Hb encodes both rewarding and aversive aspects of external stimuli, thus driving motivated behaviors and decision making. Human Hb research is still nascent but develops rapidly, alongside with the growth of neuroimaging and deep brain stimulation techniques. Not surprisingly, Hb dysfunction has been associated with psychiatric disorders, and studies in patients have established evidence for Hb involvement in major depression, addiction, and schizophrenia, as well as in pain and analgesia. Here, we summarize current knowledge from animal research and overview the existing human literature on anatomy and function of the Hb. We also discuss challenges and future directions in targeting this small brain structure in both rodents and humans. By combining animal data and human experimental studies, this review addresses the translational potential of preclinical Hb research.

Keywords: Addiction; Depression; Habenula; Human; Reward; Rodent.

Conflict of interest statement

Financial Disclosures All authors report no biomedical financial interests or potential conflicts of interest.

Figures

Figure 1
Figure 1. Habenula connectivity in rodents and humans
Key pathways connecting medial habenula (MHb) and lateral habenula (LHb), the two subdivisions of the Hb, to other brain structures. Habenula connectivity is embedded in brain circuits classically described as reward and emotion circuits, whose dysfunction is associated to psychiatric diseases reviewed here. A. Structural connectivity in animal studies: The lateral Hb (LHb) receives inhibitory inputs from the prefrontal cortex (PFC), ventral pallidum, globus pallidus (GP) and lateral hypothalamus (LH) through the stria medullaris (SM) and, in turn, sends information to monoaminergic nuclei (5). Projections of LHb to dopaminergic neurons have been best described, and include direct (ventral tegmental area (VTA), see (100)) and indirect (tail VTA, see (101, 102)) projections. A recent tracing study further revealed an equal number of LHb projections to either dopaminergic (VTA) or serotonergic (dorsal raphe (DR) and median raphe nucleus (MnR)) nuclei, which are mostly but not exclusively segregated, indicating that LHb regulates the two monoamine nuclei either independently (the vast majority of LHb projecting neurons) or jointly (few heterogeneously distributed LHb projecting neurons) (103); both projections are excitatory (11, 104). The medial Hb (MHb) circuitry is less well known. The medial nucleus receives mainly excitatory inputs from the septum, nucleus accumbens (NAc) and broca diagonal band (BDB) (4, 5). and has excitatory projections to the rostromedial tegmental nucleus (RMTg) but mainly and massively to the interpeduncular nucleus (IPN), which in turn projects to the VTA and possibly the raphe nuclei (104). Thus, both MHb and LHb regulate in turn the VTA, DRN and possibly other midbrain and hindbrain structures such as the Locus Coereulus (LC) (103). Asymmetrical projections from MHb to LHb have been described (17). B- Functional connectivity in human studies: Hb connectivity established for both forebrain (in grey) and midbrain/hindbrain (in black) structures by fMRI (10, 21, 105). Abbreviations: CPu: caudate Putamen; Hippo: Hippocampus; Amyg: Amygdala; SNC: substantia nigra compacta; PAG: periaqueductal gray; RN: Raphe Nucleus; LC: locus coeruleus; ACC: anterior cingulate cortex.
Figure 2
Figure 2. Gene transcriptome in the habenula
Genome-wide gene expression studies in rodents show differing expression patterns between LHb and MHb, as exemplified by Wagner et al. study (106) or large-scale gene mapping studies (see Allen Brain Atlas or GENSAT). In our own analysis, data extracted from both Allen Brain Atlas and Brain Star show the top-100 genes with strongest expression in mouse (left) and human (right) transcriptomes. Genes from these groups detected in lateral habenula (LHb, in grey), medial habenula (MHb, in black) or both (in yellow) are indicated. Our analysis (Figure 2) of mouse databases confirms differential gene expression in MHb and LHb, with only a small pool of common genes detected across the two Hb subdivisions. As for the mouse, our analysis of highly expressed human genes using the same AllenBrain and BrainStar databases, (Figure 2) unveils differential gene expression in LHb and MHb in the human brain, supporting the notion of separate functions for the two main Hb nuclei. Interestingly, comparison of mouse and human transcriptome data reveals a cluster of highly expressed Hb genes common to humans and rodents. This cluster includes Gpr139 encoding an orphan G protein coupled receptor and Scub1 encoding a ribosomal protein highly expressed in MHb, Tcf7l2 encoding a transcription factor best detected in LHb across species, and several other genes encoding notably the mu opioid receptor, the orphan receptor GPR151 or subunits of the nicotinic acetylcholine receptors that are well detected in both subdivisions of the Hb in rodents and humans. All these genes expressed in both species have translational value for rodent Hb research and potential clinical developments.

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