Hyperactivation of the habenula as a link between depression and sleep disturbance

Abstract

Depression occurs frequently with sleep disturbance such as insomnia. Sleep in depression is associated with disinhibition of the rapid eye movement (REM) sleep. Despite the coincidence of the depression and sleep disturbance, neural substrate for depressive behaviors and sleep regulation remains unknown. Habenula is an epithalamic structure regulating the activities of monoaminergic neurons in the brain stem. Since the imaging studies showed blood flow increase in the habenula of depressive patients, hyperactivation of the habenula has been implicated in the pathophysiology of the depression. Recent electrophysiological studies reported a novel role of the habenular structure in regulation of REM sleep. In this article, we propose possible cellular mechanisms which could elicit the hyperactivation of the habenular neurons and a hypothesis that dysfunction in the habenular circuit causes the behavioral and sleep disturbance in depression. Analysis of the animals with hyperactivated habenula would open the door to understand roles of the habenula in the heterogeneous symptoms such as reduced motor behavior and altered REM sleep in depression.

Keywords: depression; glutamate transporters; glutamates; habenula; monoamines; rapid eye movement sleep (REMS).

Figure 1

Cellular mechanism for the excessive excitability in the lateral habenular neurons. (A) Coronal section of the adult mouse brain showing the anatomical position of the medial and lateral habenulae by Nissl staining. (B) Schematic diagram showing the orientation of the MHb and LHb receiving the inputs from GPi/EPN, DB and LH and projecting to the brain stem nuclei. LHb neurons also receive ascending afferent fibers from the serotonergic raphe nuclei. (C) Schematic diagram showing molecules essential in the glutamatergic synaptic transmission. Glutamate (red dots) is transported into the synaptic vesicle at the axonal terminal of presynaptic neurons by vesicular glutamate transporter 2 (black rectangles, Vglut2). Serotonin (green dots) acts on the presynaptic axonal terminal through serotonin receptors (light green rectangles, 5-hydroxytryptamine (serotonin) receptor (5HTR)) to inhibit the excitatory transmission. Released glutamate binds and activates the a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptor containing GluR1 subunit (pink rectangles) whose recruitment to the synapse is regulated by β form of calcium/calmodulin-dependent kinase II (βCaMKII). Glutamate transporters (brown rectangles) expressed in astrocytes (GLT-1 and GLAST) and neurons (EAAC1) clear the glutamate released to synaptic cleft.

Figure 2

Regulation of the rapid eye movement (REM) sleep by habenular projection. (A) Efferent targets of the LHb in regulation of REM sleep. Schematic diagram of a sagittal section of the mouse brain showing the afferent and efferent connectivity of LHbM (red) and LHbL (blue). LHbM receives inputs preferentially from the DB and send the axons to the serotonergic raphe nuclei, dorsal and ventral tegmental nuclei containing GABAergic neurons, nucleus incertus producing the neuropeptide relaxin-3 and dopaminergic ventral tegmental area (VTA) and substantia nigra, pars compacta (SNc). On the other hand, LHbL receives inputs preferentially from GPi/EPN and LH and sends the axons to the GABAergic rostromedial tegmental nucleus (RMTg). (B) Categorization of the sleep stage into awake, REM sleep and non-REM sleep according to the electroencephalogram (EEG) and electromyogram (EMG). Blue traces in the upper three panels show raw activity in EEG (top) and EMG (bottom) during the awake (left), non-REM sleep (middle) and REM sleep (right). Lower panels show an example of classification of the sleep record based on the spectrogram of EEG (top), EMG power (middle) into the three stages (bottom). Spectrogram represents a pseudocolor plot of the power of each frequency range for each 4 s window. Note that the power in the delta (1–3 Hz) and theta (5–8 Hz) band dominates with reduced EMG power during non-REM and REM sleep period, respectively. In the awake state, high EMG power is evident.