Circuits Regulating Pleasure and Happiness in Bipolar Disorder

Abstract

According to our model, the motivation for appetitive-searching vs. distress-avoiding behaviors is regulated by two parallel cortico-striato-thalamo-cortical (CSTC) re-entry circuits that include 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, control 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); while, hyperactive motivation to exhibit behavior related to avoidance of aversive states results in dysphoria (relief leads to happiness). These two systems collaborate in a reciprocal fashion. We hypothesized that the mechanism inducing the switch from bipolar depression to mania is the most essential characteristic of bipolar disorder. This switch is attributed to a dysfunction of the lateral habenula, which regulates the activity of midbrain centers, including the dopaminergic ventral tegmental area (VTA). From an evolutionary perspective, the activity of the lateral habenula should be regulated by the human homolog of the habenula-projecting globus pallidus, which in turn might be directed by the amygdaloid complex and the phylogenetically old part of the limbic cortex. In bipolar disorder, it is possible that the system regulating the activity of this reward-driven behavior is damaged or the interaction between the medial and lateral habenula may be dysfunctional. This may lead to an adverse coupling between the activities of the misery-fleeing and reward-seeking circuits, which results in independently varying activities.

<p>Association of Cholinergic Muscarinic M4 Receptor Gene Polymorphism with Schizophrenia</p>

“…24 Moreover, many findings in human and animal studies indicate an association between cholinergic hyperactivity and bipolar depression. 25,26 The same mechanism, which in theory might involve insufficient activity of inhibitory CHRM4, might also induce suicidality in patients with schizophrenia. Therefore, we believe that the findings of Scarr et al might be related to the specific deceased patient sample they studied.…”

LPS-induced cortical kynurenic acid and neurogranin-NFAT signaling is associated with deficits in stimulus processing during Pavlovian conditioning

“…Cortical dysfunction in neuropsychiatric disorders is associated with mood disorders, depression and psychosis (Loonen et al, 2017; Shrestha et al, 2015; Sigurdsson et al, 2010). Genetic variants of Nrgn have been associated with cortical degeneration (Thong et al, 2013).…”

Beyond sports: Efficacy and safety of creatine supplementation in pathological or paraphysiological conditions of brain and muscle

“…Port et al found decreased levels of creatine and choline in the right caudate nucleus of bipolar patients compared to controls. Their finding is significant since malfunctioning of the caudate nucleus is involved in the pathogenesis of the bipolar disorder …”

“…Their finding is significant since malfunctioning of the caudate nucleus is involved in the pathogenesis of the bipolar disorder. 123,124 It is interesting to note that in a study on the antidepressant effect of tri-iodothyronine, the depressed patients who responded to this treatment also showed increased cerebral phosphocreatine levels compared to the baseline measurement. This study showed also that higher baseline levels of cerebral phosphocreatine predicted the subsequent clinical response to tri-iodotironin 125 (83% sensitivity and 75% specificity).…”