The habenulae are part of a highly conserved conduction system, the dorsal-diencephalic conduction system (DDC), that interconnects sites in the limbic forebrain with the ventral midbrain and hindbrain (Bianco & Wilson, 2009).
The paired habenula nuclei exhibit several left-right asymmetries. Displaying differences in the proportion of neuronal subtypes with distinct patterns of gene expression, axon terminal morphology and connectivity (Bianco et al, 2008, Roussigne at al, 2009).
The habenulae have been shown to be important in a range of behaviours. Their regulation of monaminergic activity in the midbrain is important for the modulation of fear behaviours, avoidance learning and attention (Agetsuma et al, 2010). As would be expected of a regulator of monoaminergic activity they also have been implicated in psychosis, depression, anxiety, schizophrenia and addictive behaviours. They also play a role in circadian rhythms, sleep initiation and duration and reproductive and maternal behaviours (Bianco & Wilson, 2009, Hikosaka, 2010).
The neuroanatomical asymmetries of the habenula can also lead to a lateralisation of certain behaviours (Barth et al, 2005).
The habenulae are spheroid nuclei. Habenular neurons are mono-polar.. The cells direct their dendrites inwards forming an internal neuropil core that the cell bodies surround.
In the zebrafish, the left habenula receives projections from the left-sided parapineal organ that promotes the elaboration of left sided habenular identity (Bianco et al, 2008).
At later stages, in both habenulae a dorsal and a ventral habenular subnucleus(vHb) can be distinguished. The ventral subnucleus is homologous to the lateral mammalian habenula and the dorsal habenula is homologous to the medial mammalian habenula. The dorsal habenula can be further subdivided into lateral and medial subnuclei (dHbL,dHBM). (Amo et al, 2010).
The habenulae are part of a system that relays information from the telencephalon and entopeduncular nucleus in the forebrain to the interpeduncular nucleus and to the raphe nucleus located in the midbrain/hindbrain. The afferent fibres from the telencephalon/ entopeduncular nucleus reach the habenulae via the stria medullaris. The projections of the habenula to the interpeduncular nucleus and raphe nucleus travel in the fasciculus retroflexus.
In zebrafish there are obvious anatomical asymmetries between the left and right habenulae. This can be seen in the differing size and shape of the neuropil in the left and right habenulae. The dHbM and dHbL subnuclei also have different size ratios on the left and the right and innervate different regions of the IPN. While the dHbm subnucleus is the main source of projections to the ventral region of the IPN the dHbL subnucleus projects mainly to the dorsal IPN (Agetsuma et al, 2010).
Single cell electroporations of habenula neurons showed that habenular efferents have two distinct patterns of axonal arborisation in their terminals in the IPN. Axons coming from the left-sided habenula neurons terminate predominantly in the dorsal IPN. Three-dimensional reconstructions of these L-typical arbors reveal them to be formed like a 'domed crown' with branches extending over considerable DV depth. Their terminals circle the IPN and extend colaterals directed internally into the IPN.Right-sided habenula neurons predominantly terminate in the ventral IPN. Their axon terminals also surround the IPN but in a more ovoid-like shape “reminiscent of an electromagnetic coil. They look a lot flatter than the L-typical arbors, extending over less depth. The branches of the right axons concentrate more in the periphery, with relatively few branches in the centre of the IPN. Although these single cell electroporation experiments have not yet been carried out in transgenic lines labeling specific habenula subnuclei the results of Bianco et al, 2008 correlate well with later studies describing the innervation of the IPN by the lateral and medial dorsal habenula nuclei.
From bulk labeling experiments, results suggest that the left habenular nucleus innervates the dorsal IPN and the right habenular nucleus innervates the ventral IPN. In Agetsuma et al, 2010 the habenula-IPN projection pattern in the adult is shown. Instead of bulk labeling the entire habenula nuclei with DiI, the dHbL and dHbm and their efferents are labeled in the double transgenic Tg(narp:GAL4VP16; UAS:DsRed2; brn3a- hsp70:GFP) fish. In the adult the Narp expression selectively labels the dHbL subnucleus, which is much larger on the left-side. Axons from this subnucleus terminate predominantly in the dorsal IPN. The Brn3a:GFP expression labels the dHbM, the terminals of these nuclei innervate the ventral IPN primarily. In the adult there is also an intermediate zone of the IPN where in the Tg(narp:GAL4VP16; UAS:DsRed2; brn3a- hsp70:GFP) red and green terminals overlap. The application of anterograde tracers to the dIPN showed that efferents from this region project to the dorsal raphé and continue on to terminate in the griseum central (GC)which corresponds to the mammalian periaqueductal gray (PAG), dorsal tegmental nucleus and nucleus incertus. These areas in mammals have been linked to the control of behaviour in fearful or stressful conditions. Manipulation of the dHbL-dIPN pathway with tetanus toxin light chain biased the fish towards a freezing behaviour as opposed to the normal flight response when subjected to cued fear-conditioning. This corroborates that in zebrafish the dHbL-dIPN –GC pathway, as in mammals, is involved in the modification of behavioral responses in an experience-dependent manner (Agetsuma et al, 2010).
Unlike the dorsal habenular nuclei the ventral habenular nuclei are symmetric, the vHb projects via the fasiculus retroflexus(FR) to the ventral part of the median raphé. The efferents travelling in the FR are arranged with the dHb efferents forming the core of the tract while the vHb efferents form a sheath surrounding them(Amo et al, 2010).
Habenula Afferent areas
By observing the expression patern of the vHB specific marker Diamine Oxidase(dao) throughout development it is possible to see that the dorso-ventral orientation of the fish habenula is a result of a morphogenetic process. At 5dpf expression of dao in the primordium is lateral to the dorsal habenular nuclei. This region then migrates ventro-medially to result in the arrangement we observe in the adult zebrafish.
is part of: epithalamus, diencephalon, forebrain
has parts: dorsal habenula nucleus, ventral habenula nucleus
Transgenic Lines/Antibodies that label this brain region
Amo et al, 2010 http://www.ncbi.nlm.nih.gov/pubmed/20107084.
Concha et al, 2003 http://www.ncbi.nlm.nih.gov/pubmed/12895418
Bianco et al, 2008 http://www.ncbi.nlm.nih.gov/pubmed/18377638
Bianco & Wilson, 2009 http://www.ncbi.nlm.nih.gov/pubmed/19064356
Hendricks & Jesuthasan 2007 http://www.ncbi.nlm.nih.gov/pubmed/17394162
Agetsuma et al, 2010 http://www.ncbi.nlm.nih.gov/pubmed/20935642
Hikosaka, 2010 http://www.ncbi.nlm.nih.gov/pubmed/20559337
Turner et al, 2016 https://www.frontiersin.org/articles/10.3389/fncir.2016.00030/full