Circuits Regulating Pleasure and Happiness-Mechanisms of Depression

Abstract

According to our model of the regulation of appetitive-searching vs. distress-avoiding behaviors, the motivation to display these essential conducts is regulated by two parallel cortico-striato-thalamo-cortical, re-entry circuits, including the core and the shell parts of the nucleus accumbens, respectively. An entire series of basal ganglia, running from the caudate nucleus on one side, to the centromedial amygdala on the other side, controls the intensity of these reward-seeking and misery-fleeing behaviors by stimulating the activity of the (pre)frontal and limbic cortices. Hyperactive motivation to display behavior that potentially results in reward induces feelings of hankering (relief leads to pleasure). Hyperactive motivation to exhibit behavior related to avoidance of misery results in dysphoria (relief leads to happiness). These two systems collaborate in a reciprocal fashion. In clinical depression, a mismatch exists between the activities of these two circuits: the balance is shifted to the misery-avoiding side. Five theories have been developed to explain the mechanism of depressive mood disorders, including the monoamine, biorhythm, neuro-endocrine, neuro-immune, and kindling/neuroplasticity theories. This paper describes these theories in relationship to the model (described above) of the regulation of reward-seeking vs. misery-avoiding behaviors. Chronic stress that leads to structural changes may induce the mismatch between the two systems. This mismatch leads to lack of pleasure, low energy, and indecisiveness, on one hand, and dysphoria, continuous worrying, and negative expectations on the other hand. The neuroplastic effects of monoamines, cortisol, and cytokines may mediate the induction of these structural alterations. Long-term exposure to stressful situations (particularly experienced during childhood) may lead to increased susceptibility for developing this condition. This hypothesis opens up the possibility of treating depression with psychotherapy. Genetic and other biological factors (toxic, infectious, or traumatic) may increase sensitivity to the induction of relevant neuroplastic changes. Reversal or compensation of these neuroplastic adjustments may explain the effects of biological therapies in treating depression.

Keywords: amygdala; basal ganglia; depression; habenula; mechanism; neuroplasticity; stress.

Figure 1

Cortical-subcortical-processing units. Extrapyramidal units are shown as an example of such cortico-striato-thalamo-cortical processing units. (A) Direct and indirect pathways lead to activation or inhibition of the anterior cortical endpoint. Abbreviations: D1, medium spiny neurons carrying dopamine D1 receptors; D2, medium spiny neurons carrying dopamine D2 receptors; DYN, dynorphin; ENK, enkephalin; GPe, globus pallidus externa; GPi, globus pallidus interna; SP, substance P; STh, subthalamic nucleus. Red arrows, excitatory; blue arrows, inhibitory. (B) Converging pathways through the basal ganglia correct the serially connected intracortical connections. Abbreviations: a, sensory input; b, motor output; c, to contralateral cortex; NS, non-specific part of the thalamus; S, specific part of the thalamus. Red, black, green, blue arrows, undetermined neurochemically.

Figure 2

Stimulation of the core and shell of the nucleus accumbens. Adapted from Dalley et al. (2008). VTA, ventral tegmental area; LC, locus coeruleus. Red arrows, glutamatergic; blue arrows, GABAergic; gray arrows, dopaminergic; green arrow, adrenergic.

Figure 3

The organization of the misery-fleeing and reward-seeking regulatory systems. The series of limbic and extrapyramidal basal ganglia that form converging processing units are separated from each other by the system that contains the nucleus accumbens. These units regulate motivations to exhibit misery-fleeing and reward-seeking behaviors. The activity of the basal ganglia processing unit is regulated by monoaminergic neurons from the midbrain, which are, in turn, controlled by the cerebral cortex, through a direct (ventral) and an indirect (dorsal) connection. The dorsal connection includes the habenula and the fasciculus retroflexus. [Note: the figure is slightly changed in Loonen and Ivanova, (submitted)]. Red arrows, glutamatergic; gray arrows, dopaminergic; purple arrows, serotonergic; green arrows, adrenergic; black arrows, undetermined neurochemically.

Figure 4

Three monoaminergic neurotransmitter systems. Adrenergic (A), serotonergic (B), and dopaminergic (C) neuropathways. Cell bodies are in the nuclei (red-filled shapes) positioned within the brainstem. Nerve fibers (red lines) terminate in the dorsal and ventral striata, amygdala, and frontotemporal cortex (Nieuwenhuys, ; Loonen, 2013b).

Figure 5

The network that regulates circadian rhythms. Retinal fibers are directly connected to the suprachiasmatic nucleus and thalamus. The suprachiasmatic nucleus is connected to the paraventricular nucleus, which influences endocrine and sympathetic activity. Sympathetic fibers from the superior cervical ganglion regulate melatonin secretion from the epiphysis. 1, retina; 2, suprachiasmatic nucleus; 3, paraventricular nucleus; 4, thalamus; 5, pineal gland; 6, raphe nuclei; 7, superior cervical ganglion. Red, orange, and blue arrows, undetermined neurochemically.

Figure 6

Relationship between the HPA axis and the immune system. The hypothalamic paraventricular nucleus (green) stimulates the production of cortisol from the adrenal gland (gray); cortisol inhibits the production of pro-inflammatory cytokines by immune cells (white and blue), by the mechanism shown in the inset. Cortisol also inhibits (−), and pro-inflammatory cytokines activate (+), the paraventricular nucleus. ACTH, adrenocorticotropic hormone; AVP, arginine vasopressin; CBG, cortisol binding globulin; CRH, corticotropin releasing hormone; GR, glucocorticoid receptor; HSP, heat shock protein; IL-1, interleukin 1; IL-6, interleukin 6; MDR pump, multidrug resistance protein (P-glycoprotein); TNFα, tumor necrosis factor alpha.

Figure 7

Competing pathological and adaptive endogenous responses to kindled seizures. Cellular components are shown for the (upper panel) proconvulsant and (lower panel) anticonvulsant biochemical (neuroplastic) reactions to a kindled seizure. Increased and decreased biochemical responses result in augmenting or inhibiting the ability of the neuronal system to display spontaneous electrophysiological activity (reproduced in an adapted form with permission from the author and publishers of Post, 2007).