Review articleThe habenula in psychiatric disorders: More than three decades of translational investigation
Introduction
Findings collected over the past few decades have provided a better understanding of the anatomy of the habenula and its function in linking forebrain to midbrain regions (Sutherland, 1982). However, it is only recently that we are beginning to appreciate its contribution in the pathophysiology of psychiatric disorders and in the control of reward processes. Located in the epithalamus near the pineal gland, the habenula is a set of well-conserved nuclei in all vertebrates that is divided into two anatomically and functionally distinct regions: the medial (MHb) and the lateral (LHb) habenula; the latter being further divided into a medial and lateral subdivision on morphologic and cytochemical grounds (Andres et al., 1999, Geisler et al., 2003). Both the LHb and MHb receive a major source of innervation through the stria medullaris (SM), and project to midbrain regions through the fasciculus retroflexus (FR). Despite sharing similar sources of afferent inputs, the LHb and MHb project to distinct areas of the midbrain and exhibit marked differences in their synaptic and cellular properties (Hikosaka, 2010). Neurons in the LHb are mostly glutamatergic, and primarily project to the rostromedial tegmental nucleus (RMTg) through the external part of the FR (Jhou et al., 2009, Brinschwitz et al., 2010, Hikosaka, 2010). On the other hand, neurons in the MHb mainly use acetylcholine and substance P as their neurotransmitters, and project down the core of the FR into the interpeduncular nucleus (IPN) (Bianco and Wilson, 2009, Hikosaka, 2010). Together with the SM and FR, the LHb and MHb form the dorsal diencephalic conduction system, a pathway involved in the regulation of reward and goal-directed behavior (Sutherland, 1982, Fakhoury et al., 2016a).
The habenula has recently received a lot of attention in psychiatric research because of its reciprocal connections with specific monoamine systems, including those for dopamine (DA) and serotonin (5-HT). Anatomically, the habenula is connected to the 5-HT system by sending outputs to serotonergic neurons of the raphe nuclei through the IPN, the main target of the MHb, or the RMTg, the main target of the LHb. Neurons of the LHb also project to DA neurons of the ventral tegmental area (VTA) and subtantia nigra pars compacta (SNc) through the RMTg, thus resulting in an indirect inhibitory effect on midbrain DA cell activity (Jhou et al., 2009, Barrot et al., 2012). However, the idea of an excitatory input from the LHb to midbrain DA neurons has not been ruled out inasmuch as direct glutamatergic projections from the LHb to the VTA have also been documented (Omelchenko et al., 2009, Goncalves et al., 2012, Brown and Shepard, 2016).
Over the past few decades, numerous studies have implicated the LHb in behavioral and cognitive processes, including pain (Cohen and Melzack, 1993), learning (Thornton and Davies, 1991), stress (Lee and Huang, 1988), anxiety (Murphy et al., 1996), sleep (Haun et al., 1992), and the regulation of maternal and reproductive behaviors (Matthews-Felton et al., 1995, Wagner et al., 1998). However, it is only following a recent study from Matsumoto and Hikosaka in 2007 that we are beginning to understand the role of this subnucleus in negative reward processing. In that study, the increased firing of LHb neurons observed in response to a no reward-predicting cue (i.e. not associated with the delivery of reward) coincided with a decreased in the activity of DA neurons in the SNc, suggesting that the LHb instructs negative reward signals to midbrain dopaminergic neurons (Matsumoto and Hikosaka, 2007). These findings ushered in a series of lesion (Morissette and Boye, 2008, Fakhoury et al., 2016a, Fakhoury et al., 2016b) and optogenetic (Shabel et al., 2012, Stamatakis and Stuber, 2012, Stamatakis et al., 2016) studies implicating the LHb in reward and aversion processes. Notably, electrolytic lesions encroaching the LHb and/or the SM resulted in large and long-lasting attenuations of the rewarding effectiveness of brain stimulation (Fakhoury et al., 2016a), and led to significant decreases of Fos-like immunoreactivity in multiple regions involved in reward (Fakhoury et al., 2016b). On the other hand, optogenetic activation of LHb projections to the RMTg (Stamatakis and Stuber, 2012) and LHb inputs from the basal ganglia (Shabel et al., 2012) and the lateral hypothalamus (Stamatakis et al., 2016) produced aversive behavioral phenotypes in place preference experiments. Evidence also suggests a role for the MHb in behavioral processes including anxiety, fear and the regulation of hedonic state (Yamaguchi et al., 2013, Hsu et al., 2014, Viswanath et al., 2014), however, more research is required to better understand the involvement of this structure in reward and aversive processing.
Given the major role of the habenula in encoding information about rewarding and aversive stimuli, it is not surprising that this structure has been linked to a variety of psychiatric disorders associated with dysregulated reward circuitry function. Notably, dysfunction of the habenula has been linked to attention deficit/hyperactivity disorder (Lee and Goto, 2013), sleep disorder (Aizawa et al., 2013), schizophrenia (Ellison, 1994, Shepard et al., 2006), substance use disorder (Baldwin et al., 2011, Velasquez et al., 2014), and mood disorders including major depression (Proulx et al., 2014) and bipolar disorder (Savitz et al., 2011). The focus of this review is on mood disorders, schizophrenia and substance use disorder. The following sections attempt to shed some light on the current state of knowledge of the habenula in these psychiatric disorders by illustrating findings from animal and human studies collected over more than three decades of translational investigation.
Section snippets
The habenula in mood disorders
Mood disorders encompass a wide array of mental illnesses from depressed moods, such as major depressive disorder (MDD), to moods that cycle between manic and depressive episodes, such as bipolar disorder (BD). Behavioral studies reveal that individuals with MDD that are currently-depressed (Pizzagalli et al., 2008, McFarland and Klein, 2009) or in complete remission (Pechtel et al., 2013) show blunted reward responsiveness. In addition, individuals with MDD exhibit reduced reward learning
The habenula in schizophrenia
Schizophrenia is a debilitating mental disorder characterized by a wide array of symptoms that are clustered into two main categories: the positive and negative symptoms. The positive symptoms of schizophrenia include delusion, hallucinations, and disorganized thoughts, whereas the negative symptoms include blunted affect, social withdrawal, and reduced emotional response (Makinen et al., 2008, Larson et al., 2010). In addition to the positive and negative symptoms, schizophrenic patients often
The habenula in substance use disorder
Substance use disorder is a chronic relapsing disorder characterized by deficits in the brain reward system leading to compulsive drug use, loss of control over drug intake, and the emergence of a negative emotional state (Koob and Le Moal, 1997). It has been conceptualized as a disorder that comprises three stages: preoccupation/anticipation, binge/intoxication, and withdrawal/negative affect (Koob and Simon, 2009, Koob, 2013). Different sources of reinforcement are associated with different
Conclusion
Despite its relatively small structure, the habenula has been the focus of an increasing number of investigations in psychiatric research. Findings presented in this review bolster the notion that the habenula undergoes functional and morphological changes in several psychiatric disorders, mainly through alterations of specific brain pathways and neurotransmitter systems. In particular, numerous studies have indicated that the habenula is hyperactive in depressive disorders, thus raising the
Financial disclosure
The author states that there are no conflict of interest to declare.
Acknowledgment
The author is recipient of an award from the Natural Sciences and Engineering Research Council (NSERC) of Canada.
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