Circadian Mechanisms Underlying Reward-Related Neurophysiology and Synaptic Plasticity

Abstract

Evidence from clinical and preclinical research provides an undeniable link between disruptions in the circadian clock and the development of psychiatric diseases, including mood and substance abuse disorders. The molecular clock, which controls daily patterns of physiological and behavioral activity in living organisms, when desynchronized, may exacerbate or precipitate symptoms of psychiatric illness. One of the outstanding questions remaining in this field is that of cause and effect in the relationship between circadian rhythm disruption and psychiatric disease. Focus has recently turned to uncovering the role of circadian proteins beyond the maintenance of homeostatic systems and outside of the suprachiasmatic nucleus (SCN), the master pacemaker region of the brain. In this regard, several groups, including our own, have sought to understand how circadian proteins regulate mechanisms of synaptic plasticity and neurotransmitter signaling in mesocorticolimbic brain regions, which are known to be critically involved in reward processing and mood. This regulation can come in the form of direct transcriptional control of genes central to mood and reward, including those associated with dopaminergic activity in the midbrain. It can also be seen at the circuit level through indirect connections of mesocorticolimbic regions with the SCN. Circadian misalignment paradigms as well as genetic models of circadian disruption have helped to elucidate some of the complex interactions between these systems and neural activity influencing behavior. In this review, we explore findings that link circadian protein function with synaptic adaptations underlying plasticity as it may contribute to the development of mood disorders and addiction. In light of recent advances in technology and sophisticated methods for molecular and circuit-level interrogation, we propose future directions aimed at teasing apart mechanisms through which the circadian system modulates mood and reward-related behavior.

Keywords: circadian; mouse models; psychiatric disorders; reward; synaptic transmission and plasticity.

Figure 1

Mesolimbic brain regions display rhythmic patterns in neural activity. The retinohypothalamic tract provides light information and consists of ipRGC projections from the retina to the SCN and DR. The SCN provides direct GABAergic input to the LHb, DmH, mPOA, and the PVT. Reward-related pathways include a dopaminergic projection from the VTA to the NAc and PFC, glutamatergic inputs from the Hipp, Amy and PFC to the NAc and GABAergic output of the NAc to the VP and VTA. Known rhythmic components of neural activity in each of the mood and reward-related extra-SCN brain regions are denoted. ipRGC, intrinsically photosensitive retinal ganglion cells; SCN, suprachiasmatic nucleus; DR, dorsal raphe nuclei; LHb, lateral habenula; DmH, dorsomedial hypothalamus; mPOA, medial pre-optic area; PVT, paraventricular thalamic nucleus; VTA, ventral tegmental area; NAc, nucleus accumbens; PFC, prefrontal cortex; Hipp, hippocampus; Amy, amygdala; VP, ventral pallidum; LC, locus coeruleus; OB, olfactory bulb.

Figure 2

Elements of dopaminergic transmission are under direct circadian control. Within the VTA-NAc circuitry, clock genes regulate the transcription of several genes involved in the synthesis, uptake, transmission and degradation of dopamine, including tyrosine hydroxylase (TH), dopamine transporter (DAT), pre-synaptic dopamine type-2 receptor (D2R), dopamine type-3 receptor (D3R), monoamine oxidase A (MAOA), and cholecystokinin (CCK). Within the NAc, diurnal rhythms in levels of the neurotransmitters, dopamine, glutamate, and GABA have been measured as well. The transcription of TH is repressed by the circadian transcription factor, CLOCK, as well as the nuclear receptor, REV-ERBα, which bind to enhancer box (E-Box) and ROR response-element (RRE) sites in the promoter region, respectively.