Elsevier

Neuroscience & Biobehavioral Reviews

Volume 80, September 2017, Pages 276-285
Neuroscience & Biobehavioral Reviews

Review article
The role of the habenula in the transition from reward to misery in substance use and mood disorders

https://doi.org/10.1016/j.neubiorev.2017.03.019Get rights and content

Highlights

  • Habenula (Hb) plays a major role in reward and aversion.

  • Lateral habenula (LHb) is involved in reward seeking.

  • Medial habenula (MHb) is involved in misery-fleeing behavior.

  • Enhanced LHb/MHb activity is implicated in the transition to addiction and depression.

Abstract

The habenula (Hb) is an evolutionary well-conserved structure located in the epithalamus. The Hb receives inputs from the septum, basal ganglia, hypothalamus, anterior cingulate and medial prefrontal cortex, and projects to several midbrain centers, most importantly the inhibitory rostromedial tegmental nucleus (RMTg) and the excitatory interpeduncular nucleus (IPN), which regulate the activity of midbrain monoaminergic nuclei. The Hb is postulated to play a key role in reward and aversion processing across species, including humans, and to be implicated in the different stages of transition from recreational drug intake to addiction and co-morbid mood disorders. The Hb is divided into two anatomically and functionally distinct nuclei, the lateral (LHb) and the medial (MHb), which are primarily involved in reward-seeking (LHb) and misery-fleeing (MHb) behavior by controlling the RMTg and IPN, respectively. This review provides a neuroanatomical description of the Hb, discusses preclinical and human findings regarding its role in the development of addiction and co-morbid mood disorders, and addresses future directions in this area.

Introduction

The habenula (Hb) (from the Latin, little rein) is a phylogenetically old structure highly conserved among vertebrates located in the dorsomedial portion of the thalamus (Benarroch, 2015, Loonen and Ivanova, 2015). The habenular nuclei are paired structures and belong to the epithalamus, which also harbors the pineal gland and the stria medullaris. The Hb is considered to be an important relay between cortical and subcortical structures implicated in emotion and reward processing (Hetu et al., 2016). The Hb receives inputs from the septum, basal ganglia, lateral hypothalamus, anterior cingulate and medial prefrontal cortex, and projects to several midbrain centers, most importantly the tail of the ventral tegmental area (also known as the rostromedial tegmental nucleus [RMTg]) and to the interpeduncular nucleus, which regulate the activity of midbrain monoaminergic nuclei (Bianco and Wilson, 2009, Herkenham and Nauta, 1977). As emotional and reward-related impairments are relevant across psychiatric disorders, particularly within addiction and mood disorders (Goya-Maldonado et al., 2015, Jentsch and Pennington, 2014), the function of the Hb in humans is of great clinical importance.

Functionally, the Hb is divided into lateral (LHb) and medial (MHb) parts (Benarroch, 2015, Klemm, 2004). The MHb is connected to the amygdalo-hippocampal system through fornix and medial septal area and to the LHb via the striatopallidal (i.e. extended) amygdala and lateral hypothalamus (Loonen and Ivanova, 2016b). The LHb plays an important role in brain reward responses, and has been linked to drug addiction, as well as reward-related processes in major depression (Matsumoto and Hikosaka, 2007, Sartorius et al., 2010). The MHb – which has not yet been studied as extensively as the LHb – has been mainly associated with the regulation of nicotine intake (Fowler et al., 2011, Salas et al., 2009) and may also be implicated in the regulation of depressive mood (Viswanath et al., 2013). It has been postulated that the LHb might be more implicated in the initial stages of recreational drug intake (associated with positive reinforcement), while the gradual shift towards compulsive drug use in addiction, strongly associated with negative affect (negative reinforcement), might be mediated by an enhanced activity of the LHb and a gradually greater involvement of the MHb (Loonen et al., 2017, Loonen et al., 2016).

The structure and function of the Hb have been mainly explored in preclinical studies using rodent and monkey models. The study of the Hb in humans has been hampered by its small size and difficulties resolving its boundaries (Ely et al., 2016, Kim et al., 2016, Lawson et al., 2013). Despite this limitation, several groups have attempted to study the Hb at conventional fMRI resolutions (Erpelding et al., 2014, Garrison et al., 2013, Ide and Li, 2011, Li et al., 2008, Noonan et al., 2011, Schiffer et al., 2012, Ullsperger and von Cramon, 2003) and more recently at high resolutions (Ely et al., 2016, Hennigan et al., 2015, Hetu et al., 2016, Lawson et al., 2016, Lawson et al., 2014, Salas et al., 2010), providing fairly consistent findings of Hb activation when studying punishment and reward processing.

The present review focuses on the neuroanatomical description of the Hb, and discussion of preclinical and human findings regarding the role of the Hb in the transition from recreational drug intake to addiction and co-morbid mood disorders. We first describe the neuroanatomical properties of the LHb and MHb together with their afferent and efferent projections. Second, we review animal studies showing how the Hb is involved in reward processes and aversive states, and how this may mediate the transition from recreational to compulsive drug use and development of co-morbid mood disorders. Third, we review neuroimaging studies investigating the structure and function of the Hb in humans, as well as its role in reward, aversive states, addiction and depression. Finally, we propose a model of transition from recreational drug use to substance use and mood disorders, we discuss the limitations of the existing findings and we offer suggestions for future work in this area.

Section snippets

Inputs

The Hb receives signals from the septum, hippocampus, ventral pallidum, lateral hypothalamus, global pallidus, and other areas of the basal ganglia (Fig. 1). The main input to the MHb comes from the septum, particularly the medial septum and the adjacent nucleus of the diagonal band of Broca (Benarroch, 2015, Klemm, 2004). The input to the MHb from these septal areas is primarily cholinergic and gamma-aminobutyric acid (GABA)ergic, although some inputs are glutamatergic (Benarroch, 2015).

Role of the LHb

The most important function of the LHb is to convey aversive states (Hikosaka, 2010). For instance, the anticipation or (unexpected) experience of air puffs in the eye have been shown to cause a strong excitation of the LHb neurons recorded by in vivo electrophysiology in monkeys (Matsumoto and Hikosaka, 2009). Notably, LHb neuronal firing occurs in response to unpredicted aversive events, also known as negative prediction errors; when a punishment could be predicted, LHb firing was much less

Transition to substance abuse and mood disorders

Drug addiction is a chronic relapsing disorder characterized by a loss of control over drug use, a high motivation for obtaining the drug, and maintaining drug use despite negative consequences (American Psychiatric Association, 2013). It has been proposed that drug addiction, in contrast to recreational drug use, involves a dysregulation of the neural circuits mediating reinforcement, reflecting two parallel mechanisms: dysfunction of the brain reward systems that normally mediate natural

Function of the habenula in human neuroimaging studies

Despite the considerable amount of data available from preclinical and experimental animal studies (Bianco and Wilson, 2009), the functional role of the Hb in humans remains largely unexplored (Ely et al., 2016, Furman and Gotlib, 2016, Hennigan et al., 2015, Hetu et al., 2016, Lawson et al., 2016, Lawson et al., 2014). An important limitation has been the small size of the structure, which is reported to be approximately 30 mm3 in each hemisphere (LHb plus MHb) post-mortem (Ranft et al., 2010

Model of gradually enhanced activity of LHb and MHb

The human prefrontal cortex is connected to the midbrain monoaminergic nuclei through a ventral route (passing through the medial forebrain bundle) and a dorsal pathway (including the habenula and RMTg/IPN). We have recently developed a model of how the activity of this dorsal connection is regulated in addiction (Loonen et al., 2017, Loonen et al., 2016) and depression (Loonen and Ivanova, 2016a). Of interest, it has been proposed that depression, and in particular bipolar depression, involves

Future perspectives

Testing our model of gradually enhanced LHb and MHb activity during the transition from recreational substance use to addiction and associate aversive states requires that future research considers a number of important factors. First of all, rodents should not be addicted when being administered a drug in the early stages, or when self-administering a drug on a regular basis. Rather, rats have to display a gradual loss of control over self-administration behavior, as is typically measured

Disclosures of conflicts/Acknowledgments

The authors declare that they have no conflict of interest.

Dr. Sescousse, Luijten, and Schellekens were all supported by individual Veni grants (016.155.218, 016.165.063 and 016.156.101, respectively) from the Netherlands Organisation for Scientific Research (NWO).

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