Evolutionary conservation of the habenular nuclei PNAS PLUS and their circuitry controlling the and 5-hydroxytryptophan (5-HT) systems

Marcus Stephenson-Jones, Orestis Floros, Brita Robertson, and Sten Grillner1 The Nobel Institute for Neurophysiology, Department of Neuroscience, Karolinska Institutet, SE-171 77 Stockholm, Sweden AUTHOR SUMMARY

To survive, all animals need to adapt pathway may be conserved as a their behavior in response to re- common mechanism for the reward- wards, fear-inducing stimuli, and based learning that allows verte- other motivating factors. Recent ev- brates to learn from their mistakes idence in mammals has suggested and avoid unwanted consequences that the habenular nuclei, neural (see Fig. P1). areas comprising the medial and In mammals, the ’s lateral habenulae and located in the source of these reward-related sig- , play a key role in these nals is the globus pallidus interna. processes, as well as in major psy- Our results also demonstrate that the chiatric diseases such as depression pallidal input to the homolog of the and schizophrenia (1). The neural lateral habenula is present in the circuitry containing these nuclei may lamprey. However, in contrast to

constitute a fundamental architec- mammals, the habenula-projecting NEUROSCIENCE ture for adaptive behavior because dorsal pallidum (DPh) is topo- the habenula is present in all classes graphically distinct from the dorsal of vertebrates. To elucidate the pallidum (DP; the homolog of the conserved habenula circuitry and globus pallidus interna) that projects approach an understanding of its to brainstem and thalamic areas in- basic function, we investigated the volved in motor control (3). Conse- organization of these nuclei in the quently, we propose that the verte- lamprey, one of the evolutionarily brate pallidum may be composed oldest vertebrates. We report here of two kinds of output nuclei, with that the detailed circuitry and con- one targeting the habenula (DPh) nectivity of the two habenular nuclei Fig. P1. Connectivity diagram showing the evolutionarily with reward-related signals that can are present in this species. This cir- conserved habenula circuitry, as observed for the lamprey influence reinforcement learning and cuitry therefore appears to have homologs of the medial (lfHb and rmHb) and lateral (rvHb motivation and another targeting formed part of the evolution’s blue- and rdHb) habenulae. The dashed line indicates the circuit brainstem and thalamic motor areas print for the vertebrate over features that have been adapted during evolution. DA, (DP) with action signals that can ei- 560 million years ago. dopamine; Hist, histamine; 5HT, 5-hydroxytryptophan; IPN, ther promote or suppress actions. interpeduncular ; lfHb, left habenula; LH, lateral Taken together, our results suggest Using a combination of techni- ; LL, lateral line receptors; MHb, medial ques to determine the molecular habenula; OB, ; Oct, octavolateral area; Pin, that the lateral habenula circuitry expression and connectivity of the parapineal organ; PT, pretectum; rdHb, right dorsal may have evolved as a crucial com- habenula, we found that homologs habenula; rmHb, right middle habenula; RMTg, rostromedial ponent of all vertebrate (i.e., equivalent structures that are mesopontine tegmental nucleus; rvHb, right ventral ha- that can influence three of the key conserved from a common ancestor) benula; Str, striatum. neuromodulatory systems for re- of the medial and lateral habenulae inforcement learning and to set are present in lampreys and that the circuitry that delivers the level of attention, arousal, and motivation. “commands” to other parts of the nervous system is homologous Genetic inactivation of the medial habenula in zebrafish and to that of mammals. As in mammals, separate populations of damage to the habenula in mammals lead to a reduced ability to neurons in the homolog of the lateral habenula project directly use contextual information to adapt the behavioral response to to the major neuromodulatory systems (dopamine, aversive stimuli (4). Our results demonstrate that the efferent , and histamine) that are known to regulate, among projections from the medial habenula to the interpeduncular other things, attention, motivation, and arousal. In addition, nucleus, a nucleus that projects to areas in the brainstem that a separate population of neurons in the lateral habenula ho- molog can influence these neuromodulatory systems indirectly through projections to a nucleus containing neurons with the Author contributions: M.S.-J., B.R., and S.G. designed research; M.S.-J., O.F., and B.R. per- inhibitory GABA, which, in turn, projects to formed research; M.S.-J. and O.F. analyzed data; and M.S.-J., B.R., and S.G. wrote the dopaminergic and serotonergic nuclei. In mammals, neu- the paper. rons in this indirect pathway are excited by aversive stimuli The authors declare no conflict of interest. or the absence of an expected reward and are thought to con- This is a Contributed submission. tribute to reinforcement learning by suppressing dopamine, 1To whom correspondence should be addressed. E-mail: [email protected]. a neurotransmitter that acts as the reinforcing signal (2). The See full research article on page E164 of www.pnas.org. presence of this circuitry in the lamprey suggests that this Cite this Author Summary as: PNAS 10.1073/pnas.1119348109.

www.pnas.org/cgi/doi/10.1073/pnas.1119348109 PNAS | January 17, 2012 | vol. 109 | no. 3 | 667–668 Downloaded by guest on September 28, 2021 regulate the response to fear, are conserved in lampreys. In Our results suggest that the habenula circuitry, including contrast, the “context” in which this circuitry is recruited appears homologs of the mammalian medial habenula and lateral to have changed during evolution. In the lamprey, the medial habenula, has been conserved throughout evolution. These nu- habenula homolog receives projections from sensory areas that clei may provide a common mechanism that all vertebrates use elicit freezing or escape behavior when activated by aversive to adapt the behavioral strategy (medial habenula) or regulate stimuli, including those from the medial olfactory bulb involved the neuromodulatory state (lateral habenula) to set, for example, in detecting scent and the light-sensitive parapineal organ. In the level of attention or arousal in response to motivating contrast, the medial habenula in mammalian species receives its stimuli. Because this circuitry is conserved and has been impli- major input from the septum, which, in turn, receives input from cated in psychiatric disease, our results also suggest it may be the hippocampus, a brain region that plays an important role in possible to study some of the features of these diseases in ver- memory formation. This suggests that during evolution, in- tebrate model systems amendable to genetic studies. tegrated contextual information from the hippocampus has taken on an important role and probably replaced the direct 1. Hikosaka O (2010) The habenula: From stress evasion to value-based decision-making. sensory innervation that is seen in the lamprey. Such a switch Nat Rev Neurosci 11:503–513. fl 2. Jhou TC, Fields HL, Baxter MG, Saper CB, Holland PC (2009) The rostromedial tegmental may have allowed mammals to adapt their behavior exibly in nucleus (RMTg), a GABAergic afferent to dopamine neurons, encodes response to the contextual situation instead of responding in- aversive stimuli and inhibits motor responses. Neuron 61:786–800. nately to a given stimulus. The medial habenula circuitry may 3. Stephenson-Jones M, Samuelsson E, Ericsson J, Robertson B, Grillner S (2011) therefore have evolved as the fundamental neural architecture Evolutionary conservation of the basal ganglia as a common vertebrate mechanism for action selection. Curr Biol 21:1081–1091. that adapts the behavioral strategy to aversive stimuli or the 4. Agetsuma M, et al. (2010) The habenula is crucial for experience-dependent contextual situation. modification of fear responses in zebrafish. Nat Neurosci 13:1354–1356.

668 | www.pnas.org/cgi/doi/10.1073/pnas.1119348109 Stephenson-Jones et al. Downloaded by guest on September 28, 2021