ReviewDREADDing the lateral habenula: A review of methodological approaches for studying lateral habenula function
Introduction
The habenular complex in the dorsal diencephalon is located on either side of the vertebrate third ventricle bilaterally. The habenular complex consists of medial and lateral sub-divisions that are morphologically and functionally distinct and have divergent connections with other brain regions (Klemm, 2004, Sutherland, 1982). Here, we focus on the lateral habenula (LHb), a brain region that is currently under intense scrutiny by neuroscientists. The LHb receives afferent projections via the stria medullaris from the limbic forebrain, which is innervated by the cerebral cortex, basal ganglia, lateral hypothalamus, and parts of the extended amygdala, among other brain regions (Geisler and Trimble, 2008). LHb efferents (via the fasciculus retroflexus) target brainstem nuclei, including the dopaminergic ventral tegmental area (VTA) and substantia nigra pars compacta, the serotonergic dorsal and median raphe nuclei, the cholinergic laterodorsal tegmentum and the GABAergic rostromedial tegmental nucleus (RMTg) (Araki et al., 1988, Geisler and Trimble, 2008, Herkenham and Nauta, 1979, Jhou et al., 2009b). Functionally, LHb lesions increase dopamine turnover in striatal and cortical terminal regions (Lecourtier et al., 2008, Lisoprawski et al., 1980, Nishikawa et al., 1986) while local electrical stimulation of the LHb inhibits spontaneous firing of VTA dopamine neurons (Christoph et al., 1986, Ji and Shepard, 2007). Serotonin neurons in the dorsal raphe nucleus are also inhibited by electrical stimulation of the LHb (Park, 1987, Wang and Aghajanian, 1977). Thus, the LHb forms a connective locus between the cortex and the midbrain that restrains the activity of several midbrain nuclei (Balcita-Pedicino et al., 2011, Brinschwitz et al., 2010, Hikosaka et al., 2008). As a result, the LHb is known to be involved in a variety of physiological and pathological responses, like reward (Gomita and Gallistel, 1982), reward error processing (Matsumoto and Hikosaka, 2007), stress (Del Bel et al., 1998, Kazi et al., 2004, Wirtshafter et al., 1994), and clinical disorders like major depression (Sartorius et al., 2010), schizophrenia (Sandyk, 1992, Shepard et al., 2006), and addiction (Beretta et al., 2012, Brown et al., 2010, James et al., 2011, Zhang et al., 2005).
The inhibitory impact of this nucleus was perplexing since most LHb projection neurons appear to be excitatory, glutamatergic neurons. However, this contradiction may be resolved by the recognition that LHb neurons frequently synapse onto GABAergic neurons, in the VTA (Omelchenko et al., 2009) or in the recently identified RMTg (Jhou et al., 2009a, Jhou et al., 2009b), which would in turn inhibit dopaminergic neuronal activity. This is intriguing since deficits in an extended network from cortical to subcortical regions, specifically in the downward inhibitory control, is thought to be an important feature of several neuropsychiatric conditions, including mood disorders and affective disorders (Price and Drevets, 2012, Volkow and Baler, 2012).
Our goal here is to review the various methodological approaches that have been used to study the function of the LHb. The reviewed studies include those that explored the LHb using lesion, electrical and chemical stimulation, in vivo microdialysis and electrophysiological approaches. We also discuss newer optogenetic and pharmacogenetic techniques and briefly highlight their advantages and disadvantages. Finally, we propose the use of viral-mediated gene transfer of DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) to further explore the function of the LHb in complex emotional behaviors and describe recent data from our laboratory demonstrating that DREADDs can serve as useful tools to manipulate LHb neuronal activity.
Section snippets
Electrophysiology
In a seminal study using an electrophysiological approach, Matsumoto and Hikosaka (2007) demonstrated that negative prediction errors result in activation of the LHb. In this study, rhesus monkeys were implanted with electrodes in the LHb (as well as in dopaminergic areas) and trained to perform right and left eye saccades that were recorded by search coils surgically implanted under the conjunctiva. A saccade to one side predicted a reward, while a saccade to the other side did not. The
Designer receptors exclusively activated by designer drugs (DREADDs)
Strategies using engineered receptors that are activated by light to manipulate LHb neuronal activity in vivo have been described in the previous section. Here, we will describe novel strategies using engineered receptors that are activated by synthetic ligands to modulate in vivo neuronal activity in the LHb in a defined spatial and temporal manner.
An approach steadily gaining in popularity is to use ligand-dependent engineered receptors called designer receptors exclusively activated by
Conclusions, Perspectives and Future Directions
The LHb is a small but intriguing brain region that appears to play an important role in integrating responses to aversive stimuli. The particular connections of the LHb have been elucidated but very little is now known about the relative contribution of each of these outputs to controlling motivated behavior and other responses to emotionally significant stimuli. In-depth microdialysis/voltametry studies to determine the effect of LHb manipulation on neurotransmitter release are warranted.
Acknowledgments
This work was supported by the National Institutes of Health DA106432 grant to J. F. N and University of Washington Alcohol and Drug Abuse Institute Research grant 65–6076 to S.G.N. The authors thank Denis Smirnov for proof-reading the manuscript.
References (67)
The efferent projections of the rat lateral habenular nucleus revealed by the PHA-L anterograde tracing method
Brain Res.
(1988)Glutamatergic axons from the lateral habenula mainly terminate on GABAergic neurons of the ventral midbrain
Neuroscience
(2010)Regional differences in the regulation of dopamine and noradrenaline release in medial frontal cortex, nucleus accumbens and caudate-putamen: a microdialysis study in the rat
Brain Res.
(1992)Lateral habenular influence on dorsal raphe neurons
Brain Res. Bull.
(1996)- et al.
Effects of reinforcement-blocking doses of pimozide on neural systems driven by rewarding stimulation of the MFB: a 14C-2-deoxyglucose analysis
Neumaier
(1982) Propensity to ‘relapse’ following exposure to cocaine cues is associated with the recruitment of specific thalamic and epithalamic nuclei
Neuroscience
(2011)The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine neurons, encodes aversive stimuli and inhibits motor responses
Neuron
(2009)Regulation of striatal serotonin release by the lateral habenula-dorsal raphe pathway in the rat as demonstrated by in vivo microdialysis: role of excitatory amino acids and GABA
Brain Res.
(1989)- et al.
The mesopontine rostromedial tegmental nucleus: an integrative modulator of the reward system
Basal Ganglia
(2011) Selective activation of the mesocortico-frontal dopaminergic neurons induced by lesion of the habenula in the rat
Brain Res.
(1980)