Habenular connections with the dopaminergic and serotonergic system and their role in stress‐related psychiatric disorders

Abstract

The habenula (Hb) is a phylogenetically old epithalamic structure differentiated into two nuclear complexes, the medial (MHb) and lateral habenula (LHb). After decades of search for a great unifying function, interest in the Hb resurged when it was demonstrated that LHb plays a major role in the encoding of aversive stimuli ranging from noxious stimuli to the loss of predicted rewards. Consistent with a role as an anti-reward center, aberrant LHb activity has now been identified as a key factor in the pathogenesis of major depressive disorder. Moreover, both MHb and LHb emerged as new players in the reward circuitry by primarily mediating the aversive properties of distinct drugs of abuse. Anatomically, the Hb serves as a bridge that links basal forebrain structures with monoaminergic nuclei in the mid-and hindbrain. So far, research on Hb has focused on the role of the LHb in regulating midbrain dopamine release. However, LHb/MHb are also interconnected with the dorsal (DR) and median (MnR) raphe nucleus. Hence, it is conceivable that some of the habenular functions are at least partly mediated by the complex network that links MHb/LHb with pontomesencephalic monoaminergic nuclei. Here, we summarize research about the topography and transmitter phenotype of the reciprocal connections 66 | METZGER ET al. 1 | INTRODUCTION Major depressive disorder (MDD) is a multifaceted disorder (Belmaker & Agam, 2008; Pizzagalli, 2014) that affected about 322 million people worldwide in 2017 (World Health Organization/WHO, 2017). MDD is characterized by low mood, lack of motivation, feelings of despair, and anhedonia-a reduced ability to experience pleasure (Willner, Scheel-Kruger, & Belzung, 2013). Importantly, MDD is highly comorbid with anxiety and addictive disorders (Swendsen et al., 2010), and it has been postulated that these disorders are closely related, as they are all characterized in part by disarrangements in the reward circuitry (Eshel & Roiser, 2010; Russo & Nestler, 2013). A relative new player in the pathogenesis of MDD, as well as in the reward circuitry, is the habenula (Hb), which interestingly now is considered not only to be involved in aversive mood states such as MDD and anxiety (

A diencephalic circuit for opioid analgesia but not positive reinforcement

“…We found that MOR activation in the LHb reverses mechanical allodynia in a model of neuropathic pain in both males and females. Together these observations support our conclusion that 9,13,14,43 . Local connectivity has also been observed with functional assays, including that TTX application decreases the frequency of sEPSC and sEPSP events in a subset of LHb neurons 16,33 and that optogenetic activation of LHb neurons induces glutamatergic EPSCs (Extended Data Fig.…”

Involvement of the lateral habenula in fear memory

“…The c-Fos pattern in the LHb is also interesting regarding its potential role as a modulator of DA transmission during fear conditioning. Indeed, the part of the LHb that we defined as "rostral" includes the LHbMA subdivision described by Andres et al (1999) which neurons send excitatory projection to VTA DA neurons (Metzger et al 2019). In addition, neurons situated in the more caudallateral region of the LHb send excitatory projection on GABA neurons of the RMTg (Petzel et al 2017) which in turn inhibit VTA DA neurons activity (Brown et al 2017).…”

The Rostromedial Tegmental Nucleus: Anatomical Studies and Roles in Sleep and Substance Addictions in Rats and Mice

“…The RMTg sends a particularly dense innervation to DAergic neurons of the VTA and the SNc, and it also innervates the serotonin-rich dorsal raphe nucleus (DRN), albeit not necessarily the serotonin neurons themselves. 24,25 There are direct as well as indirect projections of the LHb to MAergic cell groups. [26][27][28][29][30] The glutamatergic (GAergic) neurons in the LHb directly innervate DAergic and GABAergic neurons in the VTA to a comparable extent.…”